JPH0651682B2 - Method for producing uracil derivative - Google Patents

Description

TECHNICAL FIELD The present invention relates to a method for producing a uracil derivative, and more particularly to an improvement in a method for producing a uracil derivative starting from a cyanoethylamine derivative.

2. Description of the Related Art Uracil derivatives include many compounds having physiological activity such as anticancer activity, antiviral activity, antibacterial activity or insecticidal activity, and also as intermediates of compounds having such physiological activity. Not only are there many important ones, but photodimers by ultraviolet rays have been attracting attention in recent years as resist materials for integrated circuits and the like.

As a method for producing a uracil derivative, a method using a cyanoethylamine derivative as a starting material, for example, a method of reacting a cyanoethylamine derivative with an alkali metal salt of isocyanic acid in an aqueous hydrochloric acid solution is known.

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention However, in the case of this production method, since the isocyanate salt is rapidly decomposed into unstable hydrogen isocyanate in an aqueous solution of hydrochloric acid, it has relatively high crystallinity and water. It becomes difficult to react with the cyanoethylamine derivative, which is sparingly soluble in
The disadvantage is that the yield is very low.

The present invention has been made to overcome such drawbacks of the conventional method for producing a uracil derivative from a cyanoethylamine derivative as a starting material.

Means for Solving the Problems The present invention has the general formula [I]: (Wherein R ₁ is a hydrogen atom, an alkyl, aryl or vinyl group having 1 to 5 carbon atoms, R ₂ is a hydrogen atom, an alkyl or aryl group having 1 to 5 carbon atoms, Y is an oxygen atom, a sulfur atom or A compound represented by (imino group) is subjected to thermal cyclization in the presence of phosphoric acid, represented by the general formula [II]: (Wherein R ₁ , R ₂ and Y have the same meaning as defined above).

The compound represented by the general formula [I] can be produced by the following method.

That is, the compound [I] in which R ₂ is hydrogen has the general formula [II
(Wherein, _{R 1} represents a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, an aryl group or a vinyl _{group) I] NC-CH 2 CH} 2 -NH-R 1 [III] cyanoethyl amine derivative represented by the And the general formula [I
V]: (In the formula, Y represents an oxygen atom, a sulfur atom or an imino group) and a urea compound represented by the formula: The present inventors have found that the use of phosphoric acid as a mineral acid in the above reaction significantly improves the yield of compound [I].

When phosphoric acid is used, it is appropriate to use phosphoric acid as an aqueous solution of 70% by weight or more.

Orthophosphoric acid or phosphoric anhydride is usually used as phosphoric acid, but polymerized phosphoric acid such as polyphosphoric acid, metaphosphoric acid and pyrophosphoric acid may be used.

The amount of phosphoric acid used is usually 1 equivalent or more, preferably 2 to 10 equivalents, relative to the cyanoethylamine derivative.

A suitable reaction temperature is 20 to 110 ° C., and when the reaction is carried out at a temperature higher than that, the compound [I] produced is formed as described later.
And the uracil derivative [II] is obtained.

The compound [I] obtained by the above reaction can be isolated as crystals by cooling and adding water.

The uracil derivative [II] of the present invention is obtained by isolating the above compound [I] and then cyclizing it by heating (110 to 200 ° C, preferably 120 to 170 ° C) in the presence of phosphoric acid. However, the uracil derivative [II] of the present invention can also be obtained by a one-step reaction of the cyanoethylamine derivative [III] and the urea compound [IV] without isolation of the compound [I]. In this case, the uracil derivative [II] is considered to be synthesized via the compound [I]. The phosphoric acid concentration is as described above, and the reaction temperature may be initially low (preferably 20 to 110 ° C.) and then elevated to 110 to 200 ° C.

When R ₂ in the compound [I] is a group other than hydrogen, for example, when it is an alkyl group or an aryl group having 1 to 5 carbon atoms, the corresponding isocyanate compound [V] is used instead of the urea compound [IV]. Good. The reaction conditions are the same as when using a urea compound.

The cyanoethylamine derivative represented by the general formula [III] used in the present invention can be prepared, for example, by reacting acrylonitrile with amines,
Particularly preferred is a cyanoethylaminobenzene derivative.

In the general formula [III], R ₁ is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, for example, a methyl group, an ethyl group, n-
A propyl group, an isopropyl group, an n-butyl group, an n-pentyl group, an aryl group or a vinyl group is shown. The aryl group is a phenyl group, a naphthyl group or the like, and may have a substituent, for example, a lower alkyl group such as methyl or ethyl, a halogen atom, a carboxyl group, an alkoxycarbonyl group, a nitro group or a sulfone group. Examples of the vinyl group include a vinyl group, an allyl group, a 1-propenyl group and an isopropenyl group.

Specific examples of the urea compound [IV] used in the present invention include urea, thiourea and guanidine.

Examples of the isocyanic acid ester represented by the general formula [V] include methyl ester, ethyl ester, isopropyl ester, n-propyl ester, n-butyl ester, t-butyl ester or phenyl ester of isocyanic acid.

Hereinafter, the present invention will be described with reference to examples.

Example 1 10 g (68.5 mmol) of N-2-cyanoethylaniline
And 10 g (167 mmol) of urea added to 50 m of 85% phosphoric acid aqueous solution were reacted with stirring at 110 ° C. for 5 hours, and the reaction mixture was subjected to a reduced pressure treatment at 160 ° C. for 5 hours and then cooled to form. 400 m of water was added to the red solid, and the white precipitate thus deposited was collected by filtration and recrystallized from ethanol to obtain 3.3 g of 1-phenyldihydrouracil (mp: 194 to 196 ° C., IR spectrum and ¹ H- NMR is shown in FIG. 1 and FIG. 2, respectively.

Example 2 2.0 g (14 mmol) of N-2-cyanoethylaniline under anaerobic conditions 1.83 m (17) of phenyl isocyanate
mmol) and 0.5 ml of triethylamine were stirred at room temperature for 4 hours, and then 85% phosphoric acid aqueous solution 10
m, and the mixture was reacted at 130 ° C. for 6 hours under stirring. After cooling, 50 m of water was added to the reaction mixture, and the deposited precipitate was collected by filtration and recrystallized from ethanol.
1.0 g of 1,3-diphenyldihydrouracil was obtained (mp: 229-230 ° C., IR spectrum and ¹ H
-NMR is shown in Figures 3 and 4 respectively).

Example 3 35 g (0.24 mol) of N-2-cyanoethylaniline
28.9 g of isopropyl isocyanate under anaerobic conditions
(0.34 mol) and triethylamine 12.4 m
The reaction solution to which was added was stirred at room temperature for 2 hours to obtain N-isopropyl-N '-(2-cyanoethyl) -N'-phenylurea. (Mp: 76-77 ° C, IR and ¹ H-NMR
Are shown in FIG. 5 and FIG. 6, respectively).

Next, 200m of 85% phosphoric acid aqueous solution was added, and with stirring.
By reacting at 130 ° C. for 6 hours, 1-phenyl-3-isopropyldihydrouracil was obtained.

EFFECTS OF THE INVENTION According to the method of the present invention, a uracil derivative useful as a medicine, a pesticide or the like and a uracil derivative useful as an intermediate of these compounds can be easily produced in good yield under relatively mild conditions.

[Brief description of drawings]

1 and 2 are IR and ¹ H-NMR charts of ¹ -phenyldihydrouracil, FIGS. 3 and 4
The figure shows the IR and ¹ of 1,3-diphenylhydrouracil
H-NMR chart and FIGS. 5 and 6 are N-
The IR and ¹ H-NMR charts of isopropyl-N ′-(2-cyanoethyl) -N′-phenylurea are shown, respectively.

Claims (9)

[Claims] 1. A general formula [I]: (Wherein R ₁ is a hydrogen atom, an alkyl, aryl or vinyl group having 1 to 5 carbon atoms, R ₂ is a hydrogen atom, an alkyl or aryl group having 1 to 5 carbon atoms, Y is an oxygen atom, a sulfur atom or A compound represented by the general formula [II]: wherein the compound represented by imino group is heated and cyclized in the presence of phosphoric acid. (In the formula, R ₁ , R ₂ and Y have the same meanings as described above). 2. The method according to claim 1, wherein R ₁ is an aryl group. 3. The method according to claim 1, wherein Y is an oxygen atom. 4. The method according to claim 1, wherein R ₂ is a hydrogen atom. 5. The production method according to claim 1, wherein heating is performed at 120 to 170 ° C. 6. General formula [III]: NC—CH ₂ CH ₂ —NH—R ₁ [III] (In the formula, R ₁ is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, an aryl group or a vinyl group. And a cyanoethylamine derivative represented by the general formula [IV]: (In the formula, Y represents an oxygen atom, a sulfur atom or an imino group) or a general formula [V]: O = C = NR ₃ [V] (In the formula, R ₃ is the number of carbon atoms. 1 to 5 representing an alkyl group or an aryl group) is reacted in the presence of phosphoric acid in the general formula [II]: (In the formula, R ₁ and Y have the same meanings as described above, and R ₂ represents a hydrogen atom, an alkyl group or an aryl group having 1 to 5 carbon atoms). 7. The method according to claim 6, wherein R ₁ is an aryl group. 8. The method according to claim 6, wherein Y is an oxygen atom. 9. A reaction between a cyanoethylamine derivative [III] and a urea compound [IV] or an isocyanate ester [V] is previously carried out at 20 to 110 ° C., and then 110 to 200.
The method according to item 6, wherein the reaction is carried out at a temperature of ℃