JPS6191178A - 5-azauracil derivative - Google Patents

Abstract

NEW MATERIAL:A compound of the formula (R1 is H, 2-acetoxymethyl, 2- hydroxyethoxymethyl; R2 is R1 other than H; R3 is H, OH, OCH3; R4 is H, or R3 and R4 incorporate to form a single bond). USE:An agent for combatting plant viral diseases. PREPARATION:The reaction of 5-azauracil and bis(trialkyltin)oxide is carried out in a solvent such as toluene to give a bis-trialkyltin compound, then the product is dissolved in an appropriate solvent and combined with (2- acetoxyethoxy)methyl bromide to effect their reaction at -20-80 deg.C. The reaction mixture is concentrated to remove by-products, then the resultant oily product is subjected to silica-gel chromatography to effect elution with a methanol-chloroform mixed solvent. The eluate is concentrated under reduced pressure to give the objective compound.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel 5-azauracil derivative represented by the following general formula.

In the formula, R8 represents a hydrogen atom, a 2-acetoxyethoxymethyl group or a 2-hydroxyethoxymethyl group, and R2
represents a 2-acetoxyethoxymethyl group or a 2-hydroxyethoxymethyl group, R1 represents a hydrogen atom, a hydroxy group or a methoxy group, and R4 represents a hydrogen atom,
Alternatively, R3 and R4 jointly exhibit sheep bonding.

The present inventors focused on the fact that certain 5-azauracil derivatives have the effect of controlling plant virus diseases, synthesized various new 5-azauracil derivatives, and discovered that these compounds have the effect of controlling various plant virus diseases. The present inventors have discovered that the present invention has an excellent pest control effect against the genus, and have completed the present invention.

The compound represented by the above general formula of the present invention has excellent control effects against plant virus diseases such as tobacco mosaic virus disease of tomatoes, potato virus disease of tomatoes, potato virus disease of perilla leaves, and cucumber mosaic virus disease of cucumbers. It is characterized by low toxicity and no chemical damage.

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.

ACOA/,,X,□ON>riNHNLO~taOAc 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 is 3.5-azauracil (5-azaurac
il) and can be easily obtained by the method of A. Piskaia et al. [8. Piskaia and
j, Gut 5yntheticProcedures
in Nucleic Ac1d Chemistry
y (W, W.

Zorbach and R.S., Tipson, Ed.
) Vol, l+105. John Wiley & 5
ons (1968)]. 5-Azauracil and bis(
The trialkyltin) oxide is refluxed while removing the water that is trapped in the solvent.

Bis(trialkyltin) oxide and ζ is bis(tri-n-butyltin)oxide, bis() 17-n
-propyltin) oxide, bis(tri-n-ethyltin) oxide, etc. can be used. As a solvent,
Abrotic solvents such as toluene and benzene are preferred. A suitable reaction time is 1 to 72 hours.

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.

How to put the obtained bistorialyltin compound into a suitable container? The mixture is dissolved, and (2-acetoxyethoxy)methyl bromide or (2-acetoxyethoxy)methyl chloride is added thereto, followed by a stirring reaction. As the solvent, halogenated hydrocarbon solvents such as dichloroethane and dichloromethane are preferred.

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

After the obtained reaction solution is subjected to f1 condensation, it is washed to remove by-produced trialkyltin halide. The resulting oil is subjected to silica gel column chromatography and eluted with a methanol-chloroform solvent to obtain two product fractions. These product categories have structural formulas (3),
Contains water or methanol adducts shown in (5), (4), and (6).

When these product fractions are heated under reduced pressure, the compound (3
), (5), the compound 1) is the compound (
Compound (2) is obtained from the fraction containing 4) and (6), respectively.

Compounds (7) and (8) are obtained by reducing the obtained compounds (11 and (2)), respectively.
%Rh-A A 203. This is achieved by hydrogenation in a suitable solvent in the presence of a catalyst such as Raney nickel or using a hydrogenating agent such as NaBHa, NaB)ICN, etc. The solvent is ethyl acetate, tetrahydrofuran, dimethoxyethane, dioxane, or a mixture thereof.
The container is suitable. The resulting reaction solution is purified by removing the catalyst, concentrating the filtrate, and subjecting it to silica gel column chromatography to obtain dihydro forms (7) and (8) of +11 and (2), respectively.

It should be noted that the reaction for obtaining compounds (1) and (2) from the bistrialkyltin compound proceeds with good yield if carried out without removing intermediates or the like during the process.

The obtained compounds (7) and (8) are then deacetylated to obtain compounds (9) and 00), respectively. Amines such as thylamine and alkali metal hydroxides such as sodium hydroxide and potassium hydroxide are suitable for this reaction, and water-methanol, water-ethanol, water-dioxane, etc. are suitable as the solvent. 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 allIl, 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 with reference to Examples.

Example 1 2.0 g of 5-azauracil and 11.6 g (1,1 equivalent) of bis(tri-n-butyltin) oxide were added to 10 g of toluene.
0 ml, water separator (Dean-5ta)
While removing by-product water by rk trap), the mixture is heated and refluxed again. After cooling, fA condensation was performed to remove toluene, and 15
．． 6 g of an oily crude product (2,4-bis(n-butyltin)-5-azauracil) is obtained, which is used as is in the next reaction.

Example 2 3.36 g of the crude product obtained in Example 1 (theory ■2, 6
3 g of 2.4-bis(n-butyltin)-5-azauracil) was dissolved in 25 ml of dichloroethane, and a solution of 1.3 g of (2-acetoxyethoxy)methylbromide in 25 mff of dichloroethane was added dropwise while cooling with water and stirring. After the dropwise addition took about 30 minutes, the mixture was stirred at room temperature for 2 hours. The reaction solution is then concentrated, and the oily residue is washed three times with 50 mA of n-hexane to wash away hexane-soluble products such as tributyltinbromide. The oily product insoluble in hexane was purified using silica gel (Merck Kieselgel 60.7n).
~230 mesh') Separate and purify using a 200 g column. Elute with chloroform containing 5% methanol,
Obtain the product classification of the species. This is 441 mg each (
(a mixture of compound (3) and compound (5)), and 590 cm (a mixture of compound (4) and compound (6)).

These were each heated under reduced pressure (0.1 mmHg) from 1 to
When heated at 150°C for 1.5 hours, the compound (
11267■, and the latter gives the compound (21260■).

[Physical properties of compound (11)] 'H-NMR (90MIIz, CDC13):
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 (LH,s) [Physical properties of compound (2)] 'H-NMR (90MHz, CD Cj23):
2.08 (3H, s).

~3.8 (2H, m).

~4.2 (2H, m).

5.29 (2H, s).

-8,20 (IH,s).

Example 3 210 mg of compound (1) was mixed with 5% Rh-Aj! z
The mixture was poured into 50 ml of ethyl acetate together with 10'0 of Os, 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 ml of compound (7) as an oily substance.

[Physical properties of compound (7)] 'H-NMR (90 MHz, CDCl1s):
2.0? (3H,s).

2.08 (3H, s).

~3.8 (4H, m).

~4.2 (4H, m).

4.60 (2H, d.

J” 2.4H2).

4.95 (2H, s).

5.30 (2H, s).

6.68 (IH Broad) -3C-NMR (22.5MHz, CDIJ!3)
: 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 CsHz+0sNi) Calculated value (%
) C; 44.95. H;6.09. N.

12, 10 Actual value (%) Ci44.79. H;6.25. N;11
．． 84 Example 4 Compound (2) 260■ 5% Rh-AJzOs 20
Pour into tetrahydrofuran with 0■, room temperature, 3.5
After the reaction was shaken for 2 days under a hydrogen stream at atmospheric pressure, the catalyst was removed by filtration, the filtrate was concentrated, and the residue was filtrated with silica (25 g).
Purify using a column. Elution with chloroform containing 5% methanol yields 115 μm of crystalline material. Recrystallization from ethyl acetate yields compound (8).

[Physical properties of compound (8)] m, p,: 121-122°C 'H-NMR (90 MHz, CDCj!z):
2.08 (3H, s).

~3.7 (2H, m).

~4.2 (2H, m).

4.63 (2H, d.

"" 2.5Hz).

4.92 (2H, s) 11 6.64 (IH, broad), 7.92 (IH, broad) I:IC-NMR (22.5MHz, CD: +OD)
: 20.8゜55.3.64.6゜67.8.76.2 Elemental analysis? (As CIH1305N3) Calculated value (
%)C; 41.56. H; 5.67°N; 1B, 1B Actual value (%) C; 41.39. H; 5.59゜Ni1
7.93 Example 5 2,86117) 2.4-bis(tri-n-butyltin)-5-azauracil (contains a theoretical amount of 2.24 g)
, 0.77 g of (2-acetoxyethoxy)methylbromide in 50 mj! in dichloroethane at 0°C.

After stirring for 30 minutes, the mixture is further stirred at room temperature for 4 hours.

After concentrating the reaction solution, it was mixed with 100 ml of n-hexane, and -
Leave it in the refrigerator at night. 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 it through 5 g of Florisil [by-products remaining at the origin are removed by thin layer chromatography (chloroform:methanol = 9:1)]
) The filtrate is concentrated to give 0.84 g of crude product, which is then heated under reduced pressure (0.1 mmHg) at 150° C. for 1.5 hours to obtain 0.63 g of a viscous syrup.

This was mixed with tetrahydrofuran-ethyl acetate (1:1).
550μ of 5% Rh-Al2O2 was added.
．． The hydrogenation reaction is carried out for 4 days in a hydrogen stream at 5 atm. After the reaction, the catalyst is removed by filtration and, after concentration, the residue is chromatographed on 50 g of silica gel. Elution with 5% methanol chloroform yielded 90 mg of compound (7) and compound (81
Get 324 ■.

Example 6 In Example 5, 4.13 g of 2,4-bis(trilobyltin)-5-azauracil, 1.3 g of (
A similar reaction is carried out using 2-acetoxyethoxy)methylbromide (1,4 eq.) to give 1.1 g of crude product. This is heated under reduced pressure to obtain a viscous syrup of 870 cm. This was dissolved in 50 m 12 of ethyl acetate, and 550 m
After adding 5 mg of Rh-A zos, a hydrogenation reaction is carried out for 3 days in a hydrogen stream at 2.5 atm. After concentration, the residue is chromatographed on 90 g of silica gel. Elution with 5% methanol and chloroform gave 202 mg of compound (7) and 218 mg of compound (8), respectively.

Example 7 200 mg of compound (7) was mixed with 5 mff1 of triethylamine-water-methanol (2:1:10)? The mixture is stirred overnight at room temperature and, after concentration, the residue is chromatographed on 10 g of silica gel. Chloroform-methanol (4:
1), 7 volumes were discharged to obtain 104 ml of compound (9) as an oily substance.

[Physical properties of compound (9)] 'l(-NMR (90MHz, CDC13)
: ~3.7 (8H,)゛Load, S), 4.6
3 (2H, d, J = 2.64), 4.96 (L H, s), 5.28 (2 H, S), 6.26 (I H, broad) 13C-NMR (22,5 MHz, CD C1, +CD
30D): 53.2, 61.6°70.4. 70.9°7°1.2.76.2 Elemental analysis: (as CgH+JiO6) Calculated value (%)
C;41.06. H;6.51. N.

15, 9 6 Actual value (%) C; 40.07. H, 6, 58, N.

15,5 1 Example 8 Compound (812,15) is treated in the same manner as in Example 7 and then concentrated to obtain a solid. This is recrystallized from hot methanol to obtain compound α0 of 137.

[Physical properties of compound aω]

m, I): 184.5-185℃'H-NM
R (90MHz, pyridine-d5): ~3.9 (4H
, m), 4.80 (2H, d, J engineering 2.42), 5.15 (2H, s), 9.04 (IH, broad) "C-NMR (22.5 MHz, pyridine-d5
): 54.9, 61.5, ? 1.1,75.6- Elemental analysis: (CJ++ OJ, combined) Calculated value (%) C; 38.09, Ni5.86, Ni22
．． 21 Actual value (%) C, 38,04, H; 5.89, N; 21
．． 59

Claims (11)

[Claims] (1) A 5-azauracil derivative represented by the following general formula. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ 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, and R_4 represents a hydrogen atom, or R_3 and R_4 jointly form a single bond. show. (2) Formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ The compound according to claim (1), which is represented by: (3) Formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ The compound according to claim (1), which is represented by: (4) Formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ The compound according to claim (1), which is represented by: (5) Formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ The compound according to claim (1), which is represented by: (6) Formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ The compound according to claim (1), which is represented by: (7) Formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ The compound according to claim (1), which is represented by: (8) Formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ The compound according to claim (1), which is represented by: (9) Formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ The compound according to claim (1), which is represented by: Formula (10): ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ The compound according to claim (1), which is represented by: Formula (11): ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ The compound according to claim (1), which is represented by: