JPS6025972A - Production of hydantoin compound - Google Patents

Abstract

PURPOSE:To produce the titled substance useful as an intermediate of pharmaceuticals and amino acids, easily, without causing the problems of waste-water treatment, by contacting a solution containing alpha-ureidocarboxylic acid amide produced in the production of hydantoin compound, with an ion exchange resin under specific condition. CONSTITUTION:A solution containing alpha-ureidocarboxylic acid amide of formula (R1 and R2 are H, 1-6C alkyl or phenyl) produced by the ammonolysis of hydantoin in the production of hydantoin compound, is treated with an acid- type cation exchange resin at 50-120 deg.C, preferably >=70 deg.C to obtain the objective compound. The cation exchange resin may be gel-type or porous type, and is converted to the acid-type before use. The amount of the resin is preferably 1-100g per 100g of the solution to be treated. The space velocity of the solution is preferably <=3hr<-1> when the solution is passed through a fixed bed filled with the ion exchange resin.

Description

[Detailed Description of the Invention] The present invention relates to a method for producing hydantoins,
Specifically, the present invention produces hydantoins in high yield by heat-treating an α-ureidocarboxylic acid amide-containing solution obtained when producing hydantoin and its derivatives by a method known per se with a cation exchange resin. It relates to a manufacturing method.

Hydantoin conductor is a chemical product useful as an intermediate raw material for pharmaceuticals and amino acids, and various manufacturing methods are known.

When hydantoins are produced by a known method, the hydantoin is decomposed with ammonia, and α-ureidocarboxylic acid amide is simultaneously produced as a by-product as shown in the following formula (Nikkashi 9g5°+?l/- (/9A&)) is known.

(R, , R, are both hydrogen, an alkyl group with carbon number / ~ B,
In general, when producing hydantoins, more than the theoretical amount of ammonia or an ammonia compound is used to prevent a decrease in yield. Therefore, the production of α-ureidocarboxylic acid amide using the above formula is Inevitable.

On the other hand, by treating the reaction product solution containing the left (j; A method (Japanese Patent Publication No. 39-197-.2 tigoq) is also known.

However, the method of treatment with an acid solution requires a step to separate and remove the acid from the product, and on the other hand, it requires an alkali to neutralize the removed acid, and the waste water generated by the neutralization. A process for processing is also necessary. Furthermore, acid-resistant materials are required for processing tanks, piping, etc., making it difficult to use industrially.
The present inventors, who had problems when producing substituted hydantoins, conducted intensive studies to solve the above problems, and as a result,
α-Ureidocarboxylic acid amide 5-
It was discovered that 3-substituted hydantoin can be obtained in high yield by conversion to substituted hydantoin, and the present invention was completed.

That is, an object of the present invention is to provide an industrially advantageous method for producing hydantoin and its derivatives, and the purpose is to provide an α-ureidocarboxylic acid amide-containing solution obtained during the production of hydantoins according to the present invention. 50-72
This can be easily achieved by contacting with an acidic cation exchange resin under polarized conditions at 0°C.

The misfire J will be explained in detail below.

The hydantoins in "Fudatsutsu" include hydantoins and derivatives thereof, and the derivatives include hydantoins in which the 3-position is particularly substituted with an alkyl M or a phenyl group with a carbon number of methyl, ethyl, propyl, isopropyl, etc. - There is a list of substituted hydantoins. The production of these hydantoins is carried out by a method known per se, but in this method, a carbonyl compound such as anosidehyde or ketone corresponding to the target substance and a cyanide compound are mixed together with anthonia and carbon dioxide. There is a method of reacting with carbon or ammonium carbonate.

In this case, as the cyanide compound, hydrogen cyanide, cyanic acid, or alkali cyanide is used, and as the carbon Cm 7 ammonium salt, ammonium carbonate, hydrogen carbonate/monium, or ammonium carbamine is used.

In particular, the reaction of reacting a carbonyl compound, hydrogen cyanide, and ammonium carbonate to obtain a 5-substituted hydantoin was conducted by Buaherer-Bergues.
It is well known as the s) method.

Other methods include a method in which cyanohydrin obtained by reacting a carbonyl compound with hydrogen cyanide is reacted with ammonia and carbon dioxide or an ammonium carbonate salt;
Furthermore, a method in which carbon dioxide or ammonium carbonate salt is reacted with aminonitrile obtained by aminating cyanohydrin is praised.

These reactions are carried out in an aqueous solution or a reaction product solution containing a hydrous organic solvent docarboxylic acid amide is directly subjected to a 7I[] heat treatment with a cation exchange resin, and α-ureido is separated from the reaction product solution by crystallization or the like. To Carbon? The amide-containing residual liquid may be heat-treated according to the method of the present invention.

When the reaction product liquid is treated in its entirety, it is preferable to react it and bring it into contact with a cation exchange resin.

The cation exchange resin used in the present method may be either a strongly acidic cation exchange resin or a weakly acidic cation exchange resin, but a strongly acidic cation exchange resin 11i is preferred.

Further, these cation-exchange fats may be of a so-called gel type or a porous type, and upon use, they are used in an acid form. The amount of cation exchange 5irr used varies depending on the content of α-ureidocarboxylic acid amide in the solution to be treated, and cannot be uniformly determined.
When the treatment operation is carried out using the U formula, it is preferable to use lθθI of the bath solution that leaks from the treatment.

When the processing solution is supplied to a fixed bed filled with ion exchange resin and processed while being circulated, the space velocity (Sv) is
? It is preferable to carry out at hr' or less.

The heat treatment according to the present invention is carried out at 0 to 2 o'C, preferably at 70°C or higher.

If the temperature exceeds this range and the temperature is too low, the conversion of α-ureidocarboxylic acid amide to hydantoin derivatives will not take place sufficiently, while if the temperature is too high, other undesirable side reactions may occur. This is undesirable as it causes deterioration of the produced resin.

The time for heat treatment is determined as appropriate, taking into account the concentration of α-ureidocarboxylic acid amide in the treatment solution, the type of ion exchange resin used, the treatment temperature, etc., but is usually in the range of 10 minutes to 2 hours. You can choose.

After heat treatment according to the method of the present invention, the hydantoin derivative contained in the treatment liquid is recovered by separating the ion conversion resin and crystallizing it from the treatment liquid by concentration or the like. If a highly purified product is required, it may be recrystallized from methanol or the like.

As described above, according to the method of the present invention, shihydantoin derivatives can be recovered by an extremely simple operation of separating the ion-exchange resin from the treated solution, and the cyhydantoin derivative can be recovered by a process of neutralizing an acid with an alkali, It is an extremely useful method industrially because it does not require any processing steps.

Next, the method of the present invention will be explained in more detail with reference to Examples, but the present invention is not limited to the following Examples unless the gist thereof is exceeded.

Example / Methanol, 2 Og and -g in a glass four-necked flask
% ammonia water/7 g, and heat to 30°C. This was added to manzolonitrile (manufactured by Tokyo Kasei Co., Ltd., purity 9).
Section 3) 2 g and 6 g were added dropwise over a period of about 10 minutes, and at the same time carbon dioxide gas was blown in at a rate of / 7 N4/hr.

After dropping the manzolonitrile, it was aged for 2 hours and then
- 3 g of reaction product solution containing phenylhydantoin 0.
7g was obtained.

In order to remove unreacted ammonia, it was heated to 65°C, and the contents of 307#M were distilled out.

In the next step, 5-phenylhydantoin, which was crystallized by processing methanol in Naroushi before distillation, was dissolved.
/B Mitsubishi Chemical Industries, Ltd. 0 Zhu registered trademark) 309 was added, and the mixture was treated in a Vμ shaking state (A5'C:) for 7 hours and 30 minutes. After cooling to room temperature, the ion exchange resin was separated and the tear fluid was sewn to dryness in a vacuum, yielding 3.3.7 g of crystals of 5-phenylhydantoin with a melting point of 69°C (yield: 9!, 7%). was gotten.

The analysis was conducted using a liquid chromatograph, and the yield is based on the raw material manzolonitrile.

In Example/Example/, the cation exchange resin was H-type strongly acidic cation exchange resin (Mitsubishi was manufactured by Seikoka Co., Ltd., Diaion
The same procedure as in Example 1 was carried out except that PK-22g Mitsubishi Kasei Corporation (registered trademark) was used. As a result, S-phenylhydantoin 3 (# (convergence ≦96°%) was found.

Comparative Example 1 The same procedure as in Example 1 was carried out except that methanol and ion exchange resin were not added to the reaction product solution and the product was sewn to dryness in a vacuum.

As a result, 9.3 g (yield g, 3.2%) of S-phenylhydantoine was obtained.

Examples 3-6 The reaction was repeated in the same manner as in Example/ζ.

At that time, the crystallized 5-phenylhydantoinha P was separated without adding methanol to the reaction product liquid. 5-phenylhydantoin in the f solution and α−
The l'f and degree of ureidobenzoic acid amide are shown in Table/.

Table 1 also shows the concentrations of 3-phenylhydantoin and α-ureidobenzoic acid amide in the r solution before heat treatment according to the method of the present invention.

Table 7 [l*l; rPH: r-phenylhydantoin*2; α-TTBA: α-ureidobenzoic acid amide From the same reaction product solution used in Example 7-W 3-
To each soy of liquid F from which phenylhydantoin had been separated, ag of H-form cation exchange resin shown in Table 1 was added, and the mixture was treated at 6°C for 7 hours. The results are shown in Table.

Table Co [Note] *1; jPH: 5-phenylhydantoin *2
; α-UBA : α-Ureidobenzoic acid amide *3; Registered dark mark of Mitsubishi Chemical Industries, Ltd. Example 10 3M % methanol aqueous solution in a glass flask? '1
．． g jql hydrogen cyanide g,! ;I, caustic soda o
, ot, g, isobutyraldehyde, 1. After adding t and jj dropwise over 7 hours and 30 minutes, the mixture was aged for 30 minutes to obtain a reaction solution containing isobutylcyanohydrin. This reaction solution g? , 7 g was dropped into a 2 g ammonia aqueous solution (g, g) at a temperature of SO° C. over 30 minutes, and at the same time, carbon dioxide gas was blown in at a rate of N4/hr. After the reaction solution was added dropwise, it was aged for 30 minutes and S-
A reaction product solution containing inpropylhydantoin was obtained. In order to remove unreacted ammonia, simple distillation was performed to distill out about 50% by weight of the reaction product liquid.

Next, the pot residue is 70. ! 70vtl of water and a strong acidic cation exchange resin (manufactured by Mitsubishi Kasei Kogyo, Diaion PK);
-CocogH type) isl was added and treated at a temperature of 90°C for 7 hours.

After cooling, the ion exchange resin was separated into 13, and the lθO of this resin was
The activated 5-isopropylhydantoin was washed with methanol from at and dissolved, and mixed with liquid f. When the obtained 1 liquid was completely dried, crystals of S-isopropylhydantoin with a melting point/F of 5°C were obtained. 9 (yield gb, y% based on isobutylcyanohydrin) was obtained.

Comparative Example λ The same procedure as in Example IO was carried out except that water and ion exchange resin were not added to the reaction product solution containing terisoglobilhydantoin and the mixture was concentrated to dryness in a container.

As a result, 73.7 g of S-isopropylhydantoin (
Yield: 69. /person in charge) was obtained.

Sender: Mitsubishi Chemical Industries, Ltd. (1 other person -・1・-)・

Claims (1)

[Claims] (1) The α-ureidocarboxylic acid amide-containing liquid obtained during the production of hydantoins is treated with an acidic cation exchange resin at a temperature of 30 to 20°C.