JP2995293B1 - Method for producing 1,6-disubstituted-1,3,5-triazine-2,4 (1H, 3H) -dione compound - Google Patents

Abstract

[Problem] To be useful as an intermediate material for pharmaceuticals, agricultural chemicals, etc.
6-disubstituted-1,3,5-triazine-2,4 (1H,
Provided is a method for producing a 3H) -dione compound by a simple operation in a high yield. SOLUTION: The general formula: (Z is a group represented by —R ² , —NH—R ² or —N (R ² ) ₂ , R ¹ and R ² are organic groups, and R ¹ and R ² are linked to form a ring structure Thiocarbamoyl compound represented by the general formula: (Z and R ¹ have the same meanings as described above) 1,6-disubstituted-1,3,5-triazine-2,4 (1
(H, 3H) -dione compound is produced.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a 1,6- useful compound which is useful as an intermediate material for fine chemical products such as pharmaceuticals and agricultural chemicals.
Disubstituted-1,3,5-triazine-2,4 (1H, 3
The present invention relates to a novel method for producing H) -dione compounds.

[0002]

2. Description of the Related Art 1,6-Disubstituted-1,3,5-triazine-2,4 (1H, 3H) -dione compounds are structurally analogous to uracil and are used in fine chemical products such as pharmaceuticals and agricultural chemicals. It is known to be useful as an intermediate material. For example, among compounds derived from compounds having such a structure, a physiologically active substance having an antagonistic effect on serotonin receptors has been found [see Journal of Medicinal Chemistry (JM).
ed. Chem. ) ", Volume 35, Page 189 (1
992)]. As a method for producing this 1,6-disubstituted-1,3,5-triazine-2,4 (1H, 3H) -dione compound, a method in which guanidine is reacted with an N-substituted acyl cyanamide [Journal Of Chemical Society (J. Chem. Soc.) ", Twelfth
79 (1952)], a method of reacting amidine with phenoxycarbonyl isocyanate or chlorocarbonyl isocyanate [“Synthesi”
s) ", Vol. 9, p. 892 (1985)," Journal of Medicinal Chemistry (JM)
ed. Chem. ) ", Volume 35, Page 189 (1
992)]. However, all of these methods are unsuitable as practical methods because a special compound must be used as a raw material.

[0003]

SUMMARY OF THE INVENTION The present invention is an improvement of such a conventional production method, which uses a readily available compound as a raw material, and allows efficient 1,6-disubstitution by a simple operation.
An object of the present invention is to provide a method for producing a 1,3,5-triazine-2,4 (1H, 3H) -dione compound.

[0004]

Means for Solving the Problems The present inventors have prepared 1,6-
Disubstituted-1,3,5-triazine-2,4 (1H, 3
As a result of intensive studies on the method for producing the H) -dione compound, the thiocarbonyl compound has been focused on the fact that its sulfur atom is easily desulfurized by silver ions. When silver cyanate is reacted with a thiocarbamoyl compound selected from among 3-disubstituted thioureas and tri-substituted thioureas, a cyclization reaction follows the desulfurization reaction, and 1,6-disubstituted-1,3,3. They have found that a 5-triazine-2,4 (1H, 3H) -dione compound can be obtained in good yield, and have completed the present invention based on this finding.

That is, the present invention provides a compound represented by the general formula

Embedded image (Z in the formula is -R ² , -NH-R ² or -N (R ² ) ₂
Wherein R ¹ and R ² are an alkyl group or an aryl
Group, aralkyl group or heterocyclic group,
They may be the same. Wherein silver cyanate is reacted with the thiocarbamoyl compound represented by the general formula

Embedded image (Wherein Z and R ¹ have the same meanings as described above) 1,6-disubstituted-1,3,5-triazine-2,4
It is intended to provide a method for producing a (1H, 3H) -dione compound.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION In the method of the present invention, a thiocarbamoyl compound used as one of the raw materials has a structure represented by the aforementioned general formula (I), and specifically, when Z is -R General formula that is ²

Embedded image (Wherein R ¹ and R ² have the same meanings as described above), and a general formula wherein Z is —NH—R ²

Embedded image (Wherein R ¹ and R ² have the same meaning as described above), or Z is -N (R ² ) ₂
Is a general formula

Embedded image (Wherein R ¹ and R ² have the same meanings as described above).

The alkyl group in the general formulas (Ia), (Ib) and (Ic) is not particularly limited, but is preferably 1 to 20. The alkyl group may be linear, branched, or cyclic, and may have an inert substituent such as a halogen atom, a nitro group, a cyano group, or an alkoxyl group. Examples of this alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-
Butyl, tert-butyl, pentyl, hexyl, cyclohexyl, octyl, decyl, trifluoromethyl and the like.

As the aryl group, a phenyl group,
Examples include a naphthyl group and an anthryl group, which may have an inert substituent such as a halogen atom, a nitro group, a cyano group, an alkyl group, an alkoxyl group. Examples of the aryl group having this substituent include a tolyl group,
Examples include a xylyl group, a chlorophenyl group, and a methylnaphthyl group. Examples of the aralkyl group include a benzyl group, a phenethyl group, a naphthylmethyl group and the like, and these include a halogen atom, a nitro group, a cyano group, an alkyl group,
It may have an inert substituent such as an alkoxyl group. Further, examples of the heterocyclic group include a furyl group, a thienyl group, a pyrrolyl group, a pyridyl group, a morpholino group, a quinolyl group, a xanthenyl group, and the like.
It may have an inert substituent such as a halogen atom, a nitro group, a cyano group, an alkyl group and an alkoxyl group.
R ¹ and R ² may be the same or different.
It may be .

Examples of the thiocarbamoyl compound represented by the general formula (I) include thiobenzoylanilide,
1,3-diphenylthiourea, 1,3-dipyridylthiourea, morpholinothiocarbonylanilide, dimethylthiocarbonyltoluid, ε-thiocaprolactam, N-
(Chlorophenyl) thiobenzamide, chlorothiobenzoylanilide, 9-xanthenylthiocarbonyltoluid, chloroanilinothiocarbamoylmorpholine and the like.

In the method of the present invention, silver cyanate is reacted with the thiocarbamoyl compound.
It is preferably carried out in an organic solvent. As the organic solvent, for example, acetonitrile, tetrahydrofuran,
Ethyl acetate, N, N-dimethylformamide, pyridine, dichloromethane and the like can be mentioned, and these can be used alone or as a mixture of two or more.

Next, a preferred embodiment of the present invention will be described. First, in a suitable organic solvent, the compound represented by the general formula (I)
After dissolving the thiocarbamoyl compound represented by
Silver cyanate is added in an amount of usually 2 equivalents or more, preferably 2.2 to 2.5 equivalents, per 1 mol of the thiocarbamoyl compound, and the mixture is stirred and reacted at room temperature. At this time, the reaction may be promoted if necessary by heating. After completion of the reaction, the precipitated insoluble silver sulfide is removed by means such as filtration, and then the solvent is distilled off under reduced pressure. The generated target compound can be purified by a method such as recrystallization or column chromatography, if necessary. Thus, the 1,6-disubstituted-1,3,5-triazine-2,4 (1H, 3H)-represented by the general formula (II)
A dione compound is obtained.

In this reaction, as the raw material thiocarbamoyl compound, the above-mentioned general formula (Ia) and general formula (I-
b) or when using general formula (Ic), the corresponding 1,6-disubstitution represented by general formula (II-a), (II-b) or (II-c) below -1,3,5
-Triazine-2,4 (1H, 3H) -dione compound is obtained.

Embedded image (R ¹ and R ² have the same meaning as above)

The reaction mechanism in the present invention can be estimated as described below.

Embedded image (R ¹ and Z have the same meaning as above)

The 1,6-disubstituted-1,3,5-triazine represented by the general formula (II) obtained by the method of the present invention
Specific examples of the 2,4 (1H, 3H) -dione compound are shown below.

Embedded image

The identity of the compound obtained was 1,3-
The compound (c) obtained from diphenylthiourea was analyzed by X-ray crystallography, and the compound (b) obtained from N- (4-chlorophenyl) thiobenzamide was a known substance. The comparison was performed with literature values. Other compounds (a), (d)-
(F) was performed by measuring the melting point, elemental analysis, and infrared absorption spectrum.

[0016]

According to the present invention, various thiocarbamoyl compounds and silver cyanate, which are easily available, are used as raw materials under mild conditions near room temperature by a novel reaction mode which has not been known before. , 6-Disubstituted-1,3,5-triazine-2,4 (1H, 3H) -dione compounds can be produced simply and in good yield. 1,6-disubstituted-1,3,5-triazine-2,4 obtained by the method of the present invention
(1H, 3H) -dione compounds are useful as intermediate materials for fine chemical products such as pharmaceuticals and agricultural chemicals. For example, since the compound is structurally a uracil-like compound, it can be used for producing a compound having a physiological activity other than a serotonin receptor antagonistic action.

[0017]

EXAMPLES Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.

EXAMPLE 1 Thiobenzoylanilide in 4 ml of acetonitrile
While stirring the solution in which 0 mmol was dissolved, 360 mg (2.4 mmol) of silver cyanate was added little by little to this. After stirring the reaction solution at room temperature for 3 hours, the reaction temperature was increased and the reaction was further carried out under reflux for 1 hour. After the reaction,
The precipitated silver sulfide was filtered off while hot, the solvent in the obtained filtrate was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate: hexane volume ratio 1: 1:
1) By purification, 1,6-diphenyl-1,
3,5-Triazine-2,4 (1H, 3H) -dione (Compound A) was obtained in 85% yield. The melting point (mp), infrared absorption spectrum (IR) and elemental analysis results of this compound are as follows. mp: 236 ° C., IR (cm ⁻¹ ): 3045 (N−
H), 1747 (C = O), 1699 (C = O). Elemental analysis: Found (%); C, 68.01; H, 4.22; N, 15.75 Calculated (%); C, 67.92; H, 4.18; N, 15.84.

Example 2 1- (4-chlorophenyl) -6 was prepared in the same manner as in Example 1 except that N- (4-chlorophenyl) thiobenzamide was used instead of thiobenzoylanilide. -Phenyl-1,3,5-triazine-
2,4 (1H, 3H) -dione (compound b) was obtained. Mp of this compound is 239 to 240 ° C. [Literature: 235 to 240 ° C.
238 ° C; “Journal of Chemical Society (J. Chem. Soc.), P. 279 (19)
52 years]], and the yield was 62%.

Example 3 In the same manner as in Example 1, except that 1,3-diphenylthiourea was used in place of thiobenzoylanilide, 1-phenyl-6-phenylamino-1, 3,5-Triazine-2,4 (1H, 3H) -dione (compound C) was obtained in a yield of 76%. The mp, IR and elemental analysis results of this compound are as follows. mp: 246 ° C, IR (cm ^-1 ): 3244 (N-
H), 3155 (N-H), 1732 (C = O), 16
89 (C = O). Elemental analysis: Found (%); C, 64.18; H, 4.30; N, 19.93 Calculated (%); C, 64.28; H, 4.32; N, 19.99.

Example 4 In the same manner as in Example 1 except that 4-chlorothiobenzoylanilide was used instead of thiobenzoylanilide, 1-phenyl-6- (4-
Chlorophenyl) -1,3,5-triazine-2,4
(1H, 3H) -dione (compound D) was obtained in a yield of 78%. The mp, IR and elemental analysis results of this compound are as follows. mp: 225 ° C, IR (cm ^-1 ): 3173 (N-
H), 3052 (N-H), 1736 (C = O), 17
09 (C = O). Elemental analysis: measured value (%); C, 60.02; H, 3.34; N, 13.86 calculated value (%); C, 60.11; H, 3.36; N, 14.02

Example 5 1- (4-methylphenyl)-was obtained in the same manner as in Example 1 except that 9-xanthenthiocarbonyl-p-toluid was used instead of thiobenzoylanilide. 6- (xanthen-9-yl) -1,3,
5-Triazine-2,4 (1H, 3H) -dione (compound e) was obtained in 46% yield. Mp, IR of this compound
And the results of elemental analysis are as follows. mp: 248 ° C, IR (cm ^-1 ): 3140 (N-
H), 3032, 2825, 1753 (C = O), 16
82 (C = O), 1576, 1261 (C-O). Elemental analysis: Found (%); C, 72.10; H, 4.45; N, 10.94 Calculated (%); C, 72.05; H, 4.47; N, 10.96.

Example 6 In the same manner as in Example 1 except that 4-chloroanilinothiocarbamoylmorpholine was used instead of thiobenzoylanilide, 1- (4-chlorophenyl) -6- ( Morpholino-1) -1,3,5-
Triazine-2,4 (1H, 3H) -dione (Compound F) was obtained in 89% yield. The mp, IR and elemental analysis results of this compound are as follows. mp: 227 ° C, IR (cm ^-1 ): 3225 (N-
H), 3059 (NH), 1730 (C = O), 16
99 (C = O). Elemental analysis: measured value (%); C, 50.61; H, 4.21; N, 17.99 calculated value (%); C, 50.58; H, 4.24; N, 18.15

──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Kazumasa Honda 1-1-1, Higashi, Tsukuba, Ibaraki Pref., National Institute of Advanced Industrial Science and Technology (56) Reference: Journal of Medicinal Chemistry; vol. 35 (No. 1) pp. 189-194 (1992) (58) Fields investigated (Int. Cl. ⁶ , DB name) C07D 251/20 C07D 251/46 C07D 405/04 CAPLUS (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] 1. A compound of the general formula (Z in the formula is -R ² , -NH-R ² or -N (R ² ) ₂
Wherein R ¹ and R ² are an alkyl group or an aryl
Group, aralkyl group or heterocyclic group,
However, they may be the same or different. Wherein silver cyanate is reacted with a thiocarbamoyl compound represented by the formula: (Wherein Z and R ¹ have the same meanings as described above) 1,6-disubstituted-1,3,5-triazine-2,4
A method for producing a (1H, 3H) -dione compound.