JP2003096047A - Production method of ureido derivative and production method of barbituric acid derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a production method of ureido derivatives which can stably produce high-purity ureido derivatives at a high yield and a production method of barbituric acid derivatives which can stably produce high-purity barbituric acid derivatives in high yield. SOLUTION: A ureido derivative represented by general formula [III] is characteristically produced as follows: A compound represented by general formula [I] is reacted with a compound represented by general formula [II] in the presence of an amine-based base, and after the reaction is finished, extraction washing or suspension washing is carried out so that the content of the amine-based in the ureido derivative produced may be 0.1% or below. In formulas, R1 is a substituent, n is an integer of 0 to 5, R2 is an alkyl group, aryl group or heteroaryl group and X is an anion atom.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing an ureido derivative and a barbituric acid derivative useful as intermediates for organic synthetic compounds and functional dyes.

[0002]

2. Description of the Related Art It is known that ureido derivatives, which are versatile as intermediates for organic synthetic compounds, can be obtained from isocyanate derivatives and amine derivatives. When the amine derivative forms an ammonium salt,
It is common to neutralize with a base in advance. For example, Collect. Czech. Chem. Commu
In the case of glycine ester hydrochloride in Vol. 51, pp. 375-390 (1986), a method of neutralizing with triethylamine in the coexistence with an isocyanate derivative and then reacting is described.

As a method of synthesizing a barbituric acid derivative, a method of reacting a ureido derivative and malonic acid in the presence of an acid anhydride is generally known.

However, when a barbituric acid derivative is synthesized by the known barbituric acid derivative synthesis method using the ureido derivative synthesized by the known ureido derivative synthesis method, depending on the quality of the ureido derivative used, This is a problem because the cyclization reaction rate deteriorates, the yield of barbituric acid derivative production decreases, and the quality of the produced barbituric acid derivative deteriorates.

[0005]

The present invention has been made in view of the above circumstances, and an object of the present invention is to provide a ureido derivative and a barbituric acid derivative which can be stably produced in high yield and high purity. And a method for producing a barbituric acid derivative.

[0006]

The above object of the present invention can be achieved by the following constitutions.

1. Production by reacting the compound represented by the general formula [I] with the compound represented by the general formula [II] in the presence of an amine base, and washing with extraction water or suspension water after completion of the reaction. The method for producing the ureido derivative represented by the general formula [III], wherein the content of the amine base in the ureido derivative is 0.1% or less.

2. The method for producing the ureido derivative according to the above 1, wherein the reaction is carried out in an ester solvent or an aromatic hydrocarbon solvent.

3. The ureido derivative represented by the general formula [III] obtained by the production method described in 1 or 2 is reacted with the compound represented by the general formula [IV] in the presence of an acid anhydride. A method for producing a barbituric acid derivative represented by the general formula [V].

4. The method for producing a barbituric acid derivative according to the above item 3, wherein the barbituric acid derivative represented by the general formula [V] is a barbituric acid derivative represented by the general formula [VI].

5. The barbituric acid derivative represented by the general formula [VI] obtained by the production method described in 4 above is hydrolyzed without isolation, and thus the general formula [VI]
[I] A method for producing a barbituric acid derivative.

The present invention will be described in detail below. In the general formulas [I] to [VII], examples of the substituent represented by R ₁ include an alkyl group, a cycloalkyl group, an alkenyl group, an aryl group, an acylamino group, a sulfonamide group, an alkylthio group, an arylthio group, Halogen atom,
Heterocyclic group, sulfonyl group, sulfinyl group, phosphonyl group, acyl group, carbamoyl group, sulfamoyl group, cyano group, alkoxy group, aryloxy group, heterocyclic oxy group, siloxy group, acyloxy group, carbamoyloxy group, amino group, Examples thereof include an alkylamino group, an imide group, a ureido group, a sulfamoylamino group, an alkoxycarbonylamino group, an alkoxycarbonylamino group, an aryloxycarbonylamino group, an alkoxycarbonyl group, an aryloxycarbonyl group and a carboxyl group. These groups may be further substituted, for example, a group similar to R ₁ may be substituted.

Examples of the alkyl group represented by R ₂ , R ₃ , R ₄ and R ₅ include a methyl group, an ethyl group, a propyl group, an isopropyl group, a tert-butyl group, a hexyl group, an octyl group and a dodecyl group. Hexadecyl group, 2-ethylhexyl group, cyclohexyl group and the like can be mentioned. These groups may be further substituted, for example, a group similar to R ₁ may be substituted. R ₂ is -L ₁ CO
OR ₅ group (wherein L _1, R ₅ has the general formula [VII] and L _1, R ₅ in each synonymous) is preferably.

Examples of the aryl group represented by R ₂ , R ₃ , R ₄ and R ₅ include a phenyl group, a 1-naphthyl group, 2
A naphthyl group and the like. These groups may be further substituted, for example, a group similar to R ₁ may be substituted.

Examples of the alkylene group represented by L ₁ include methylene group, ethylene group, propylene group, butylene group, pentylene group, octylene group, decylene group and the like.

Examples of the arylene group represented by L ₁ include groups such as phenylene group and naphthalene group.

The general formula [III] of the invention of claim 1 of the present invention
The method for producing the ureido derivative represented by
The compound represented by the formula [II] is reacted with the compound represented by the general formula [II] in the presence of an amine base, and after completion of the reaction, washing with extraction water or suspension water is performed to produce an amine-based ureido derivative. It is characterized in that the content of the base is 0.1% or less.

In the invention of claim 1 of the present invention, when the compound represented by the general formula [I] and the compound represented by the general formula [II] are reacted in the presence of an amine base, The amount of the compound represented by the formula [I] is preferably 0.5 to 2.0 mol, and 1.0 to 1.3 mol, relative to 1 mol of the compound represented by the general formula [II]. More preferably, it is used in the range.

When the compound represented by the general formula [I] and the compound represented by the general formula [II] are reacted with each other, the amount of the amine-based base coexisted is the compound represented by the general formula [II]. It is preferably used within a range of 0.1 to 4.0 mol, and more preferably within a range of 0.5 to 1.5 mol, relative to 1 mol.

The reaction temperature is usually preferably 50 to 150 ° C, more preferably 60 to 120 ° C.

Examples of amine bases include triethylamine, dimethylaniline, pyridine, lutidine, tetramethylguanidine and the like. Of these, particularly preferred is triethylamine.

The solvent used in the reaction is appropriately selected from ester type and aromatic type depending on the concentration of the reaction solution or the reaction temperature, and a preferable solvent is selected. Specific examples of the ester solvent include methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl carbonate, ethyl carbonate and the like. Further, examples of the aromatic hydrocarbon solvent include toluene, xylene, mesitylene and the like. Among these, preferred solvent is ethyl acetate,
It is toluene, more preferably ethyl acetate.

In the invention of claim 1 of the present invention, the content of the amine base of the ureido derivative produced by washing with water for extraction or suspension (washing with crystals for suspension) after the reaction is completed. It is characterized by being 0.1% or less, that is, 0 to 0.1%, but preferably 0% or more and 0.08% or less. When the content of the amine base exceeds 0.1%, a side reaction is induced during the cyclization ring closure reaction during the synthesis of the barbituric acid derivative production and many impurities (eg, acetylbarbituric acid, acetylhydantoin, hydantoin, etc.) are generated. ) Is produced as a by-product, resulting in a decrease in purity and a decrease in yield. As the lower limit, the smaller the content of the amine base is, the more preferable, but the purification for that is complicated and the cost may be disadvantageous.

The content of the amine base can be calculated from the proton intensity ratio measured by NMR.

The method for producing a barbituric acid derivative according to the invention of claim 3 of the present invention comprises the ureido derivative represented by the general formula [III] obtained by the production method of the invention of claim 1 or 2 of the invention. The compound represented by the general formula [IV] is reacted in the presence of an acid anhydride.

In the invention of claim 3 of the present invention, when the ureido derivative represented by the general formula [III] is reacted with the compound represented by the general formula [IV] in the presence of an acid anhydride, the reaction temperature is 50 ° C. to 150 ° C. is preferable, and 50 ° C. to 110 ° C. is more preferable.

The amount of the compound represented by the general formula [IV] is 1 mol of the ureido derivative represented by the general formula [III].
On the other hand, it is preferably used in the range of 0.5 to 1.5 mol, and particularly preferably used in the range of 0.9 to 1.3.

The amount of the acid anhydride to 1 mol of the compound represented by the general formula [IV] is preferably in the range of 0.5 to 4.0, but is preferably in the range of 1.5 to 2.5. Particularly preferred.

The addition method according to the third aspect of the present invention is to add the ureido derivative represented by the general formula [III], the compound represented by the general formula [IV] and the acid anhydride from the beginning. It is also good, but put the acid anhydride into the reaction vessel,
[I] and the compound represented by the general formula [IV] are preferably added in this order.
After the reaction of the compound represented by
It is particularly preferable to add and react the ureido derivative represented by the formula [I].

The method for producing a barbituric acid derivative according to the invention of claim 5 of the present invention is the method for producing a barbituric acid derivative represented by the general formula [VI] obtained by the method of claim 4 of the present invention. It is characterized by being hydrolyzed without being separated.

In the invention of claim 5 of the present invention, when the barbituric acid derivative represented by the general formula [VI] is hydrolyzed without isolation, the reaction temperature for hydrolysis is 10 to 12
0 degreeC is preferable, More preferably, it is 20-80 degreeC.

The solvent used in the hydrolysis reaction is water,
Examples thereof include alcohol solvents and aromatic solvents, with water and methyl alcohol being preferred.

The amount of the base or acid is 1 mol based on 1 mol of the barbituric acid derivative represented by the general formula [VI].
It is preferably used in the range of 0 to 5, but 2.0 to
It is particularly preferable to use it in the range of 4.0.

The catalyst used for the hydrolysis may be an acid or a base, and examples thereof include hydrochloric acid, sulfuric acid, sodium hydroxide, potassium hydroxide and sodium carbonate.

Of these, sodium hydroxide and potassium hydroxide are preferred. In the invention of claim 5 of the present invention, “without isolation” means that the barbituric acid derivative represented by the general formula [VI] is reacted with the barbituric acid derivative represented by the general formula [VI] after completion of the production reaction. It means to obtain the barbituric acid derivative represented by the general formula [VII] by conducting the following hydrolysis reaction and hydrolysis without taking it out from the system.

The general formulas [I] to [III] of the present invention are described below.
Typical specific examples of the compound represented by are shown below, but the present invention is not limited thereto.

[0037]

[Chemical 5]

[0038]

[Chemical 6]

[0039]

[Chemical 7]

[0040]

[Chemical 8]

The following are the general formulas [IV] to [VII] of the present invention.
Typical specific examples of the compound represented by are shown below, but the present invention is not limited thereto.

[0042]

[Chemical 9]

[0043]

[Chemical 10]

[0044]

[Chemical 11]

[0045]

[Chemical 12]

[0046]

[Chemical 13]

[0047]

[Chemical 14]

[0048]

EXAMPLES The present invention will be specifically described below with reference to examples, but the embodiments of the present invention are not limited thereto.

Example 1 1-1. << Synthesis of Exemplified Compound III-1 >> (Invention) reaction path

[0050]

[Chemical 15]

Glycine ethyl hydrochloride (14.6 g) and phenyl isocyanate (11.9 g) were added to ethyl acetate (56 ml), and triethylamine (10.6 g) was added dropwise at 40 ° C. or lower with stirring.

After completion of the dropping, the mixture is heated and stirred and refluxed for 1 hour to complete the reaction, and then allowed to cool. The precipitated triethylamine hydrochloride was filtered off, and the ethyl acetate solution of the filtrate was diluted with 70 ml of water to 2 times.
Wash with water twice.

After that, the ethyl acetate solution is cooled with ice and the precipitated crystals of the target substance are collected by filtration, washed with 15 ml of water twice and dried. 15.8 g (yield 71%) of Exemplified Compound III-1, which was the target compound, was obtained. Melting point 116 to 121 ° C. The content of the amine base (triethylamine) in this product was measured by NMR, and was calculated from the proton intensity ratio of NMR of the ethyl group of triethylamine and the ethyl group of Exemplified compound III-1. It was 05 mol%.

1-2. << Synthesis of Exemplified Compound III-1 >>
(Invention) The reaction is performed in the same manner as in 1-1 above, the reaction is completed, and the mixture is allowed to cool. The precipitated triethylamine hydrochloride was filtered off, and this time, the ethyl acetate solution of the filtrate was not washed with water as it was, and the ethyl acetate solution was ice-cooled to collect the crystals of the target substance to be precipitated, and the crystals were collected with 15 ml of water. Wash twice and then crystallize with water 1
The mixture is suspended and stirred in 00 ml, filtered, collected, washed twice with 15 ml of water, and then dried. Exemplified compound III-1, which is the object
15.4 g (yield 70%) was obtained. Melting point 116-121
C. The content of the amine base (triethylamine) in this product was measured by NMR, and was calculated from the NMR proton intensity ratio of the ethyl group of triethylamine and the ethyl group of Exemplified compound III-1, and was 0.08 mol%. there were.

1-3. << Synthesis of Exemplified Compound III-1 >>
(Invention) The reaction is performed in the same manner as in 1-1 above, the reaction is completed, and the mixture is allowed to cool. The precipitated triethylamine hydrochloride is filtered off, and the ethyl acetate solution of the filtrate is washed twice with 70 ml of water.

After that, the ethyl acetate solution was ice-cooled and the precipitated crystals of the target substance were collected by filtration and washed with 15 ml of water twice.
After that, the crystals are suspended and stirred in 100 ml of water, then collected by filtration, washed twice with 15 ml of water, and then dried. 15.3 g (yield 69%) of Exemplified Compound III-1, which was the object, was obtained. Melting point 116 to 121 ° C. The content of the amine base (triethylamine) in this product was measured by NMR, and was calculated from the proton intensity ratio of NMR of the ethyl group of triethylamine and the ethyl group of Exemplified compound III-1. It was 01 mol%.

1-4. << Synthesis of Exemplified Compound III-1 >>
(Comparison) Reaction is performed in the same manner as in 1-1 above, the reaction is completed, and the mixture is allowed to cool. The precipitated triethylamine hydrochloride was filtered off, and this time, the ethyl acetate solution of the filtrate was not washed with water as it was, and the ethyl acetate solution was ice-cooled to collect the crystals of the target substance to be precipitated, and the crystals were collected with 15 ml of water. Wash twice, then dry.
Exemplified compound III-1, 16.0 g (yield 72)
%) Was obtained. Melting point 116 to 121 ° C. The content of the amine base (triethylamine) in this product was measured by NMR, and was calculated from the proton intensity ratio of NMR of the ethyl group of triethylamine and the ethyl group of Exemplified compound III-1. It was 16 mol%.

2-1. << Synthesis of Exemplified Compound VI-1 >> (Present Invention) Reaction Pathway

[0059]

[Chemical 16]

5.7 g of malonic acid in 12.3 g of acetic anhydride
Is added and the mixture is reacted at 60 ° C. for 1 hour, 11.1 g of Exemplified Compound III-1 obtained in 1-1 above is added, and the mixture is reacted at 80 ° C. for 3 hours. After completion of the reaction, pour into warm water at 50 ° C and pour with potassium carbonate.
It is made H9 and extracted with 50 ml of ethyl acetate. The aqueous layer was acidified with concentrated hydrochloric acid, extracted with 50 ml of ethyl acetate, washed with water, concentrated, and dissolved in 30 ml of ethyl acetate to prepare n-hexane (3).
Add 0 ml and reconnect. Exemplified compound VI-1, 1 of interest
1.6 g (yield 80%) was obtained. Melting point 113-117 ° C 2-2-2-4. << Synthesis of Exemplified Compound VI-1 >> (2-2
2-3 (invention), 2-4 (comparative)) Instead of the exemplary compound III-1 obtained in the above 1-1, the exemplary compound III obtained in the above 1-2, 1-3 or 1-4. -1
Exemplified compound VI-1 was synthesized in the same manner as in 2-1 except that the same amount of each compound was used.
-1 was 11.0 g (yield 76%), 12.
3 g (yield 85%) and 8.7 g (yield 60%) were obtained.

Table 1 shows the above process and results.

[0062]

[Table 1]

3-1. << Synthesis of Exemplified Compound VII-1 >>
(Invention) Reaction route

[0064]

[Chemical 17]

5.7 g of malonic acid in 12.3 g of acetic anhydride
Was added and reacted at 60 ° C. for 1 hour to prepare Exemplified Compounds III-1, 1
Add 1.1 g and react at 80 ° C. for 3 hours.

After completion of the reaction, the mixture is poured into warm water at 50 ° C., adjusted to pH 9 with potassium carbonate, and extracted with 50 ml of ethyl acetate. The aqueous layer is separated, 7 g of sodium hydroxide is added, and the mixture is reacted (hydrolyzed) at room temperature for 1 hour. After completion of the reaction, the mixture is neutralized with concentrated hydrochloric acid and extracted with 50 ml of ethyl acetate. After concentration with ethyl acetate, recrystallization was performed with ethyl acetate: n-hexane = 1: 1 to obtain 9.6 g (yield 73%) of Exemplified Compound VII-1 as a target product. Melting point 178 to 182 ° C. Identification of each compound in Examples was carried out by MASS and NMR spectra, and it was confirmed that each compound was a target compound.

As is apparent from the examples of the present invention and the comparative examples, it can be seen that the ureido derivative and barbituric acid derivative can be stably produced in high yield and high purity by the production method of the present invention.

[0068]

According to the present invention, it is possible to provide a method for producing a ureido derivative and a method for producing a barbituric acid derivative, which are capable of stably producing a ureido derivative and a barbituric acid derivative with high yield and high purity.

Claims (5)

[Claims] 1. A compound represented by the following general formula [I] and a compound represented by the following general formula [II] are reacted in the presence of an amine base, and after completion of the reaction, extraction with water or washing with suspension is carried out. The method for producing the ureido derivative represented by the following general formula [III] is characterized in that the content of the amine base in the produced ureido derivative is 0.1% or less. [Chemical 1] (In the formula, R ₁ represents a substituent, n represents an integer of 0 to 5. When n is 2 or more, R ₁ may be the same or different. R ₂ is an alkyl group, an aryl group or Represents a heterocyclic group, and X represents an anion atom.) 2. The method for producing a ureido derivative according to claim 1, wherein the reaction is carried out in an ester solvent or an aromatic hydrocarbon solvent. 3. A reaction between the ureido derivative represented by the general formula [III] obtained by the production method according to claim 1 and the compound represented by the following general formula [IV] in the presence of an acid anhydride. A method for producing a barbituric acid derivative represented by the following general formula [V], which comprises: [Chemical 2] (In the formula, R ₁ represents a substituent, n represents an integer of 0 to 5, and when n is 2 or more, R ₁ may be the same or different. R ₂ is an alkyl group or an aryl group. Or a heterocyclic group, and R ₃ and R ₄ each represent a hydrogen atom, an alkyl group or an aryl group.) 4. The barbituric acid derivative represented by the general formula [V] is a barbituric acid derivative represented by the following general formula [VI]. Method for producing derivative. [Chemical 3] (In the formula, R ₁ represents a substituent, n represents an integer of 0 to 5. When n is 2 or more, R ₁ may be the same or different. R ₃ and R ₄ are each hydrogen. Represents an atom, an alkyl group or an aryl group, L ₁ represents an alkylene group or an arylene group, and R ₅ represents an alkyl group or an aryl group.) 5. The barbituric acid derivative represented by the general formula [VI] obtained by the production method according to claim 4 is hydrolyzed without isolation, and the following general formula [VI] is used.
[I] A method for producing a barbituric acid derivative. [Chemical 4] (In the formula, R ₁ represents a substituent, n represents an integer of 0 to 5. When n is 2 or more, R ₁ may be the same or different. R ₃ and R ₄ are each hydrogen. Represents an atom, an alkyl group or an aryl group, and L ₁ represents an alkylene group or an arylene group.)