JPH0471070B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a novel 5-
Relating to azauracil derivatives.

In the formula, R ₁ represents a hydrogen atom, a 2-acetoxyethoxymethyl group or a 2-hydroxyethoxymethyl group, and R ₂ represents a 2-acetoxyethoxymethyl group or a 2-hydroxyethoxymethyl group.
R ₃ represents a hydrogen atom, hydroxy group or methoxy group, R ₄ represents a hydrogen atom, or R ₃ and
R ₄ together represent a single bond.

The present inventors focused on the fact that certain 5-azauracil derivatives exhibit plant virus disease control effects, synthesized various new 5-azauracil derivatives, and discovered that these compounds are effective against various plant virus diseases. The present invention was completed based on the discovery that it has an excellent control effect against the genus.

The compound represented by the above general formula of the present invention can be used to treat tobacco mosaic virus disease of tomato, dwarf dwarf virus disease of tomato, dwarf dwarf virus disease of the true leaves of Japanese rubella
It exhibits an excellent control effect against plant virus diseases such as cucumber mosaic virus disease of cucumber, and is characterized by low toxicity and no phytotoxicity.

The compounds of the present invention will be described below.

The compound of the present invention is represented by the above general formula, and specific examples thereof are as follows.

Hereinafter, the compounds of the present invention will be indicated by the above compound numbers.

Next, a method for synthesizing the compound of the present invention will be described.

The starting material was 5-azauracil (5-
azauracil) and can be easily obtained by the method of A. Piskaia et al. [A. Piskaia and J. Gut
Synthetic Procedures in Nucleic Acid
Chemistry (WW Zorbach and RSTipson,
Ed.) Vol. 1, 105, John Wiley & Sons (1968)]. 5-Azauracil and bis(trialkyltin) oxide are refluxed in a solvent while removing by-product water.

As bis(trialkyltin) oxide,
Bis(tri-n-butyltin) oxide, bis(tri-n-propyltin) oxide, bis(tri-n-ethyltin) oxide, etc. can be used. Preferred solvents are aprotic solvents such as toluene and benzene. The reaction time is 1
~72 hours is appropriate.

The obtained reaction product is concentrated to remove the solvent to obtain a crude bistrialkyl tin compound. This is used as it is in the next reaction.

The obtained bistrialkyltin compound is dissolved in a suitable solvent, and (2-acetoxyethoxy)methyl bromide or (2-acetoxyethoxy)methyl chloride is added to perform a stirring reaction. As a solvent,
Preferred are halogenated hydrocarbon solvents such as dichloroethane and dichloromethane.

The reaction temperature is suitably -20 to 80°C, and the reaction time is suitably 1 to 20 hours.

After concentrating the obtained reaction solution, it is washed to remove by-produced trialkyltin halide. The resulting oil was subjected to silica gel column chromatography and eluted with a methanol-chloroform solvent to obtain two product fractions. Each of these product categories contains water or methanol adducts of structural formulas (3), (5) and (4), (6).
When these product fractions are heated under reduced pressure, compound (1) is converted from the fraction containing compounds (3) and (5), and compound
Compound (2) is obtained from the classification containing (4) and (6), respectively.

When the obtained compounds (1) and (2) are reduced, the compound
(7) and (8) are obtained, respectively. This reduction is 5%
This can be achieved by hydrogenation in the presence of a catalyst such as Rh-Al ₂ O ₃ or Raney Nickel or in a suitable solvent using a hydrogenating agent such as NaBH ₄ or NaBHCN. Suitable solvents are ethyl acetate, tetrahydrofuran, dimethoxyethane, dioxane, or a mixed solvent thereof. The resulting reaction solution was purified by removing the catalyst, concentrating the filtrate, and subjecting it to silica gel column chromatography, resulting in (1) and
Dihydro derivatives (7) and (8) of (2) are obtained, respectively.

In addition, from the above-mentioned bistrialkyltin compound,
The reactions to obtain (1) and (2) proceed with good yield when carried out without removing intermediates etc. during the reaction.

Next, the obtained compounds (7) and (8) are deacetylated to obtain compounds (9) and (10), respectively. This reaction can be accomplished by stirring at room temperature in the presence of a base. Bases used include amines such as triethylamine, sodium hydroxide,
Alkali metal hydroxides such as potassium hydroxide are suitable, and suitable solvents include water-methanol, water-ethanol, water-dioxane, and the like. After concentrating the resulting reaction solution, it is purified by silica gel column chromatography or recrystallized using hot methanol or the like to obtain compounds (9) and (10), respectively.

An example of the manufacturing process for the compound of the present invention is as follows.

The present invention will be explained in more detail below using Examples.

Example 1 2.0 g of 5-azauracil and 11.6 g (1.1 equivalents) of bis(tri-n-butyltin) oxide were dissolved in 100 ml of toluene, and a water separator (Dean-Stark
Heat and reflux overnight while removing by-product water using a trap. After cooling, concentrate to remove toluene, 15.6
g of an oily crude product [2,4-bis(n-butyltin)-5-azauracil] is obtained. This will be used as is in the next reaction.

Example 2 3.36 g of the crude product obtained in Example 1 (theoretical amount
2.63 g of 2,4-bis(n-butyltin)-5-
Dissolve 1.3 g of (2-acetoxyethoxy)methyl bromide in 25 ml of dichloroethane while cooling on ice and stirring.
Drop the solution. After dropping it for about 30 minutes, leave it at room temperature for 2 minutes.
Stir for an hour. The reaction solution is then concentrated, and the oily residue is washed three times with 50 ml of n-hexane to remove hexane-soluble products such as tributyltin bromide. The oily product insoluble in hexane is separated and purified using a 200 g column of silica gel (Merck Kieselgel 60, 70-230 mesh). Elution with chloroform containing 5% methanol gives two product fractions.
This is 441 mg (mixture of compound (3) and compound (5)) and 590 mg (mixture of compound (4) and compound (6)), respectively.
It is an oily substance. When these are heated at 150°C for 1 to 1.5 hours under reduced pressure (0.1 mmHg),
Compound (1) 267mg from the former, compound (2) 260mg from the latter
is obtained.

[Physical properties of compound (1)] ¹ H-NMR (90MHz, CD Cl ₃ ): 2.06 (3H, s),
2.08 (3H, s), ~3.8 (4H, m), ~4.2 (4H,
m), 5.28 (2H, s), 5.46 (2H, s), 8.15 (1H,
s).

[Physical properties of compound (2)] ¹ H-NMR (90MHz, CD Cl ₃ ): 2.08 (3H, s),
~3.8 (2H, m), ~4.2 (2H, m), 5.29 (2H,
s), 8.20 (1H, s).

Example 3 210 mg of compound (1) and 100 mg of 5% Rh-Al ₂ O ₃ were poured into 50 ml of ethyl acetate, and a hydrogenation reaction was carried out for 2 days at room temperature under a hydrogen stream of 2 atm. After the reaction, the catalyst is removed by filtration, concentrated, and purified using a silica gel column (25 g). Elution with chloroform containing 3% methanol yields about 106 mg of compound (7) as an oily substance.

[Physical properties of compound (7)] ¹ H-NMR (90MHz, CD Cl ₃ ): 2.07 (3H, s),
2.08 (3H, s), ~3.8 (4H, m), ~4.2 (4H,
m), 4.60 (2H, d, J = 2.4Hz), 4.95 (2H,
s), 5.30 (2H, s), 6.68 (1H broad). ^13C -NMR (22, 5MHz, _CDCl3 ): 20.8, 53.2,
63.1, 63.4, 66.9, 67.7, 71.2, 76.1, 152.9,
153.8, 170.7, 170.8.

Elemental analysis: (as C ₈ H ₂₁ O ₈ N ₃ ) Calculated value (%) C; 44.95, H; 6.09, N; 12.10 Actual value (%) C; 44.79, H; 6.25, N; 11.84 Example 4 Compound (2) 260 mg was poured into tetrahydrofuran together with 200 mg of 5% Rh-Al ₂ O ₃ and shaken at room temperature under a hydrogen stream of 3.5 atm for 2 days. After the reaction, the catalyst was removed by filtration, the filtrate was concentrated, and the residue was purified with silica gel (25 g).
Purify using a column. Elution with chloroform containing 5% methanol yields 115 mg of crystalline material. Recrystallization from ethyl acetate yields compound (8).

[Physical properties of compound (8)] mp: 121-122°C ^1H -NMR (90MHz, _CDCl3 ): 2.80 (3H, s), ~
3.7 (2H, m), ~4.2 (2H, m), 4.63 (2H, d,
J=2.5Hz), 492 (2H, s), 6.64 (1H, broad), 7.92 (1H, broad) ^13C -NMR (22.5MHz, _CD3OD ): 20.8, 55.3,
64.6, 67.8, 76.2 Elemental analysis: (as C ₈ H ₁₃ O ₅ N ₃ ) Calculated value (%) C; 41.56, H; 5.67, N; 18.18 Actual value (%) C; 41.39, H; 5.59, N; 17.93 Example 5 2.86g of 2.4bis(tri-n-butyltin)-5
- Azauracil (contains a theoretical amount of 2.24 g), 0.77 g
(2-acetoxyethoxy)methyl bromide of
The mixture was stirred in 50 ml of dichloroethane at 0°C for 30 minutes, and then further stirred at room temperature for 4 hours. After concentrating the reaction solution
Mix with 100 ml of n-hexane and leave in the refrigerator overnight. The hexane is removed by decantation, and the surface of the insoluble matter is washed twice with 50 ml of n-hexane. Next, dissolve this in chloroform and filter through 5 g of Florisil [thin layer chromatography (chloroform:
By-products remaining at the origin are removed using methanol (9:1). ) The filtrate was concentrated to give 0.84 g of crude product, which was then concentrated under reduced pressure (0.1 mmHg).
Heat at 150°C for 1.5 hours to obtain 0.63 g of viscous syrup. This was dissolved in tetrahydrofuran-ethyl acetate (1:1), 550 mg of 5% Rh-A ₂ O ₃ was added, and a hydrogenation reaction was carried out for 4 days in a hydrogen stream at 2.5 atmospheres. After the reaction, filter to remove the catalyst, concentrate,
The residue is chromatographed on 50 g of silica gel. 5%
Compound (7)90 was eluted with methanol and chloroform.
mg and 324 mg of compound (8) are obtained.

Example 6 In Example 5, 4.13 g of 2,4-bis(tri-n-butyltin)-5-azauracil, 1.3 g
A similar reaction is carried out using (2-acetoxyethoxy)methyl bromide (1.4 equivalents) to obtain 1.1 g of crude product. This is heated under reduced pressure to obtain 870 mg of viscous syrup. This was dissolved in 50 ml of ethyl acetate, 550 mg of 5% Rh-A ₂ O ₃ was added, and a hydrogenation reaction was carried out for 3 days in a hydrogen stream at 2.5 atmospheres. After concentration, the residue is chromatographed on 90 g of silica gel.
Compounds were eluted with 5% methanol chloroform.
202 mg of compound (7) and 218 mg of compound (8) were obtained, respectively.

Example 7 200 mg of compound (7) was added to 5 ml of triethylamine.
Stir in a water-methanol (2:1:10) mixture overnight at room temperature, concentrate and chromatograph the residue on 10 g of silica gel. Elution with chloroform-methanol (4:1) yields 104 mg of compound (9) as an oil.

[Physical properties of compound (9)] ¹ H-NMR (90 MHz, CD Cl ₃ ): ~3.7 (8H, broad, s), 4.63 (2H, d, J = 2.64), 4.96
(1H, s), 5.28 (2H, s), 6.26 (1H, broad) ^13C -NMR (22.5MHz, CD Cl + CD ₃ OD):
53.2, 61.6, 70.4, 70.9, 71.2, 76.2 Elemental analysis: (as C ₉ H ₁₇ N ₃ O ₆ ) Calculated value (%) C; 41.06, H; 6.51, N; 15.96 Actual value (%) C; 40.07, H: 6.58, N: 15.51 Example 8 215 mg of compound (8) was treated in the same manner as in Example 7 and then concentrated to obtain a solid. This was recrystallized from hot methanol to obtain 137 mg of compound (10).

[Physical properties of compound (10)] mp: 184.5-185°C ^1H -NMR (90MHz, pyridine- _d5 ): ~3.9 (4H,
m), 4.80 (2H, d, J = 2.42), 5.15 (2H,
s), 9.04 (1H, broad) ^13C -NMR (22.5MHz, pyridine- _d5 ): 54.9,
61.5, 71.1, 75.6 Elemental analysis: (as C ₆ H ₁₁ O ₄ N ₃ ) Calculated value (%) C; 38.09, H; 5.86, N; 22.21 Actual value (%) C; 38.04, H; 5.89, N; 21.59.

Claims (1)

[Claims] 1. A 5-azauracil derivative represented by the following general formula. In the formula, R ₁ represents a hydrogen atom, a 2-acetoxyethoxymethyl group or a 2-hydroxyethoxymethyl group, R ₂ represents a 2-acetoxyethoxymethyl group or a 2-hydroxyethoxymethyl group, and R ₃ represents a hydrogen atom, represents a hydroxy group or a methoxy group, R ₄ represents a hydrogen atom, or
R ₃ and R ₄ jointly represent a single bond. 2 formula: The compound according to claim 1, which is represented by: 3 formula: The compound according to claim 1, which is represented by: 4 formula: The compound according to claim 1, which is represented by: 5 Formula: The compound according to claim 1, which is represented by: 6 Formula: The compound according to claim 1, which is represented by: 7 Formula: The compound according to claim 1, which is represented by: 8 Formula: The compound according to claim 1, which is represented by: 9 Formula: The compound according to claim 1, which is represented by: 10 Formula: The compound according to claim 1, which is represented by: 11 Formula: The compound according to claim 1, which is represented by: