JPH0212464B2 - - Google Patents

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 acids, and are compounds that are not only useful as physiologically active substances, but also useful as intermediates in the production of β-phenylalanine derivatives. Conventionally, methods for producing β-phenylserines include 1) a method in which a copper complex of glycine and benzaldehyde are reacted (for example, as described in the West German patent);
960722). 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.
Another well-known method is 2) reacting glycine and benzaldehyde in the presence of an alkali and then treating with acid to produce β-phenylserine. For example, Kenneth N.F.
ShaW and Sidney W.Fox, Journal of
American Chemical Society, 75 , 3419 (1953)
According to , β-phenylserine was obtained in 70% yield by reacting glycine and benzaldehyde in water in the presence of sodium hydroxide and then treating with hydrochloric acid. However, as described in the above-mentioned literature, this method uses N-benzylidene-β, which is a reaction product of glycine and benzaldehyde.
- There is a major problem in that the sodium salt of phenylserine precipitates at once, and the reaction mixture solidifies as a whole, making mechanical stirring impossible. In addition, this reaction has the reaction formula
As shown in (1), 1 mol of benzaldehyde is first condensed with 1 mol of glycine to form N-benzylidene glycine, and this compound is further added to 1 mol of benzaldehyde to form N-benzylidene-β-
Phenylserine is produced. By treating this N-benzylidene-β-phenylserine with an acid, the desired β-phenylserine is produced. Therefore, the reaction requires 2 to 1 mole of glycine.
mole of benzaldehyde is required, of which 1 mole is the intermediate product N-benzylidene-β-phenylene. In the process of acid treatment, lucerin is regenerated as benzaldehyde, but in the conventional method, in order to separate this regenerated benzaldehyde from the product β-phenylserine, β-phenylserine crystals are washed with alcohol. The adhering benzaldehyde is removed. Therefore, it also has the disadvantage that recovery of benzaldehyde from the liquid from which β-phenylserine is 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 intensive studies on industrial production methods based on such conventional problems in the production of β-phenylserines. As a result, the above-mentioned problems can be solved by carrying out the method for producing β-phenyl serine in which glycine and benzaldehyde are reacted in the presence of an alkali and then treated with an acid in the coexistence of a hydrophobic organic solvent. I discovered that. In other words, it was discovered that the difficulty of mechanical stirring when carrying out a reaction in a water-only system was solved, and at the same time it was possible to recycle benzaldehyde with an extremely simple operation without the need for complicated recovery operations. , arrived at the method of the present invention. That is, in the method of the present invention, after reacting glycine and benzaldehydes in the presence of an alkali,
In a method for producing β-phenyl serine by acid treatment, this method is characterized in that the reaction is carried out in a mixed solvent of water and a hydrophobic organic solvent. The raw material benzaldehyde used in the method of the present invention is unsubstituted or substituted benzaldehyde, and the substituents of the substituted benzaldehyde include a lower alkyl group, a lower alkoxy group, an aryloxy group, a benzyloxy group, a halogen atom, It has a nitro group, cyano group or phenyl group, and there are no particular limitations on the substitution position and the number of substituents. Examples of benzaldehydes include o-tolualdehyde, m-tolualdehyde, p-tolualdehyde, p-ethylbenzaldehyde, o-anisaldehyde, m-anisaldehyde, p-anisaldehyde, 3,4-methylenedioxybenzaldehyde, m-phenoxybenzaldehyde,
m-benzyloxybenzaldehyde, p-benzyloxybenzaldehyde, 3,4-dibenzyloxybenzaldehyde, o-chlorobenzaldehyde, m-chlorobenzaldehyde, p-chlorobenzaldehyde, o-bromobenzaldehyde, m-bromobenzaldehyde, p-bromobenzaldehyde , 2,4-dichlorobenzaldehyde, 3,4-dichlorobenzaldehyde, o
-Nitrobenzaldehyde, m-nitrobenzaldehyde, p-nitrobenzaldehyde, p-cyanobenzaldehyde, p-diphenylaldehyde and the like. The amount of these benzaldehydes to be used is 2 moles or more, preferably 2.0 to 3.0 moles relative to glycine. The hydrophobic organic solvent used in the method of the present invention is one that dissolves benzaldehydes and is inert to the reaction, and may have some mutual solubility with water, but forms two layers: an aqueous layer and an organic layer. There are no particular restrictions as long as you do so. Specifically, hydrocarbon solvents such as benzene, toluene, xylene or ethylbenzene, halogenated hydrocarbons such as methylene chloride, dichloromethane, chloroform, carbon tetrachloride, dichloroethane, dichloroethylene, trichloroethylene, chlorobenzene, o-dichlorobenzene or trichlorobenzene. Solvents, alcoholic solvents such as 1-butanol, 2-butanol, isobutanol, 1-pentanol, 2-pentanol, 3-pentanol, 1-heptanol, 2-heptanol or 3-heptanol, diethyl ether, dipropyl Examples include ether solvents such as ether or diisobutyl ether, ketone solvents such as methyl isobutyl ketone or diisobutyl ketone, and ester solvents such as acetate or phosphate esters, but are of course limited to these. isn't it. These solvents are usually used alone, but
Even if two or more types are used as a mixture, there is no problem in the reaction. The amount of these organic solvents to be 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 due to the reaction operation, it is usually 0.3 to 20 times the weight of the benzaldehyde,
It is preferably used in a range of 0.5 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. There is no particular restriction on the ratio of water and organic solvent in this mixed solvent, but preferably the organic solvent is in an amount of 20 to 500 parts by weight per 100 parts by weight of water. Further, in the method of the present invention, the reaction is 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 used is at least the theoretical amount, but it is preferably used in the range of 1.2 to 3.0 equivalents. Of course, even if more than 3.0 equivalents are used, there is no problem with the reaction, but the amount of acid used in the acid treatment after the reaction increases, which is not very practical. 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, benzyltrimethylammonium chloride, benzyltriethylammonium chloride, benzyltributylammonium chloride, tetrabutylammonium hydrogen sulfate or trioctylmethylammonium chloride, and tetrabutylphosphonium chloride. , tetrabutylphosphonium bromide, hexadecyltributylphosphonium chloride or ethyltrioctylphosphonium bromide. The amount of these phase transfer catalysts used may be a catalytic amount, and specifically, the amount of 0.01 to 2.0 g per 100 g of glycine as a raw material is sufficient. By adding these phase transfer catalysts as necessary, the reaction is promoted and the yield of β-phenyl serine is improved. The effect of adding this phase transfer catalyst is particularly remarkable when the amount of alkali used is 1.5 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 by adding them in any order. As an example, after charging glycine, water, an organic solvent in which an aldehyde is dissolved, and if necessary a phase transfer catalyst, an alkali in the form of a solid or aqueous solution is charged or added dropwise under stirring to carry out the reaction. Reaction temperature and time: 0 to 80℃, 3 to 50 hours,
Preferably, the temperature is 10 to 60°C for 5 to 30 hours. In this way, an alkali salt of N-benzyritene-β-phenylserine is produced. In the method of the present invention, the alkali metal or alkaline earth metal salt of N-benzylidene-β-phenylserine produced by the above reaction can be easily treated with the following acid treatment without isolating it from the reaction system. It can be isolated as β-phenylserines. That is, when the reaction mass for producing N-benzylidene-β-phenylserine is added with mineral acid in an amount equal to or more than the total equivalent of 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 into a mineral acid salt, that is, the amount that is sufficient to combine glycine and benzaldehyde. This is more than the total equivalent of the alkali and glycine used in the reaction. On the other hand, by this acid treatment operation, the N-benzylidene group is hydrolyzed and the benzaldehyde by-product is 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 crystals of β-phenylserine, which are isolated by filtration. In this way, β-phenylserine can be produced in substantially pure form and at a good yield. On the other hand, it is not necessary to recover the benzaldehyde dissolved therein, and the organic solvent layer can be recycled 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
The problem of separating phenylserines and benzaldehydes has the advantage that they can be easily separated by a liquid separation operation by dissolving β-phenylserines in the aqueous layer and benzaldehydes in the organic solvent layer using mineral acid salts. Additionally, there is no need to recover the benzaldehyde from the organic solvent layer, and the organic solvent layer can be recycled and reused by simply replenishing the amount of benzaldehyde that has actually been consumed in the reaction. This is a major feature of the invention. As described above, the method of the present invention can solve all the problems of the prior art at once and simplify the manufacturing process, and has great significance as an industrial manufacturing method. Hereinafter, the present invention will be explained in more detail with reference to Examples. Example 1 60g of glycine, 400g of water, 212g of benzaldehyde
g and 120 g of toluene. 177.8 g of 45% sodium hydroxide was added dropwise over approximately 2 hours while stirring at 10 to 15°C. Thereafter, the reaction temperature was gradually raised to 20°C, and the reaction was carried out at 20 to 25°C for 20 hours. After the reaction, 292.0 g of 35% hydrochloric acid was added dropwise over 45 minutes at a temperature below 40°C, and the mixture was further stirred at room temperature for 1 hour. After standing still, the lower aqueous layer was separated by liquid separation and analyzed by high performance liquid chromatography. As a result, the production rate of β-phenylserine was 92.6% (relative to glycine). The aqueous layer was neutralized to pH=6 with 45% sodium hydroxide at room temperature, cooled to 0 to 5°C, stirred at the same temperature for 1 hour, filtered, washed with cold water, and dried under reduced pressure at 50°C. White crystals of β-phenylserine (g) were obtained. The purity analysis of this product using high performance liquid chromatography was 90.5%, and the result of differential thermal analysis confirmed that it had one molecule of water of crystallization. Yield 82.0% (based on glycine) Melting point: 198-200℃
(Decomposition) Elemental analysis value (%) Calculated value as C H N C ₉ H ₁₃ NO ₄ 54.26 6.57 7.03 Measured value 54.18 6.37 7.15 Example 2 Benzaldehyde 89.0 was added to the toluene layer of the recovered benzaldehyde obtained in Example 1. g
The reaction was carried out in the same manner as in Example 1 except that 130.6 g of β-phenylserine was obtained. Example 3 In Example 1, 200 g of dichloroethane was used instead of toluene, and 200 g of dichloroethane was used instead of 45% sodium hydroxide.
224g of 50% potassium hydroxide and reaction temperature and time
The same procedure as in Example 1 was carried out except that the temperature was 30-35°C for 18 hours to obtain 129.5 g of β-phenylserine.
Purity 90.9%, yield 8.12% (based on glycine). Example 4 60 g of glycine and 8 g of sodium hydroxide are added and dissolved in 500 g of water. Next, after adding 0.5g of trioctylmethylammonium chloride
Benzaldehyde 169.6 with stirring at 25-30 °C
A solution prepared by dissolving 150 g of toluene in 150 g of toluene was added dropwise over about 1 hour, and the reaction was further carried out at 25 to 35°C for 20 hours. After the reaction, 209 g of 35% hydrochloric 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 is separated, and the aqueous layer is heated to 45% at room temperature.
Neutralize with sodium hydroxide until pH = 6, then heat to 1 at 0-5℃.
After stirring for a while, rinse with cold water and dry.
125.3g of β-phenylserine was obtained. Purity 90.6
%, yield 78.3% (based on glycine) Examples 5 to 8 A β-phenylserine synthesis reaction 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 carried out according to the method of Example 1 using various substituted benzaldehydes instead of benzaldehyde. The results are shown in Table-2.

【table】

[Table] Example 14 In Example 1, the amount of sodium hydroxide used was 1.5 and 2.1 equivalents to glycine, and 0.5 g of trioctylbenzylammonium chloride was added as a phase transfer catalyst to each of them to cause a reaction, and after the reaction, treatment with hydrochloric acid was performed. Table 3 shows the results of a comparison of the β-phenylserine production rate in the aqueous layer obtained with the simultaneous test without the addition of a phase transfer catalyst.

【table】

Claims (1)

[Claims] 1. When glycine and benzaldehydes are reacted in the presence of an alkali and then treated with an acid to produce β-phenylserines, the reaction is performed in a mixed solvent consisting of water and a hydrophobic organic solvent. A method for producing β-phenylserines, characterized by: 2. The method according to claim 1, wherein the reaction is a reaction in the presence of a phase transfer catalyst.