JPH0216309B2 - - Google Patents

Description

[Detailed description of the invention]

This invention is a method for producing pyrrolopyrimidines, which are new compounds. More specifically, the invention provides the formula [In the formula, R ¹ is an alkyl group having 1 to 4 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, a cycloalkyl group having 5 to 7 carbon atoms, an aralkyl group having 7 to 10 carbon atoms, or

[Formula] (R ² represents an alkyl group having 1 to 4 carbon atoms or a halogen atom, n is 0, 1, 2
Or 3. ) represents a group. ] is characterized by reacting an aminomaleimide represented by the formula with phosgene or chloroformic acid trichloromethyl ester in the presence of pyridine. 2- ^hydroxy -3,4,6,7-tetrahydro-4,5,7-trioxo-5H-pyrrolo[3,4-d ] This is a method for producing pyrimidines. Pyrrolopyrimidines represented by the formula [] are
It is a new compound and is useful as a medicine, agrochemical, and an intermediate thereof. It is particularly useful as an agricultural and horticultural fungicide against rice leaf blight. Specific examples of aminomaleimides represented by the formula [] include 3-amino-1-methyl-4-
(Methylcarbamoyl)maleimide, 3-amino-1-ethyl-4-(ethylcarbamoyl)maleimide, 3-amino-1-propyl-4-(propylcarbamoyl)maleimide, 3-amino-1
-Butyl-4-(butylcarbamoyl)maleimide, 1-allyl-3-(allylcarbamoyl)-
4-Aminomaleimide, 3-amino-1-cyclohexyl-4-(cyclohexylcarbamoyl)
Maleimide, 3-amino-1-benzyl-4-
(benzylcarbamoyl)maleimide, 3-amino-1-phenyl-4-(phenylcarbamoyl)maleimide, 3-amino-1-chlorophenyl-4-(chlorophenylcarbamoyl)maleimide, 3-amino-1-dichlorophenyl- 4-
(dichlorophenylcarbamoyl)maleimide and the like. In the method of this invention, the reaction of the aminomaleimide represented by the formula [] with phosgene or trichloromethyl chloroformate in the presence of pyridine is preferably carried out using a solvent.
Any solvent may be used as long as it is inert to the reaction in the method of this invention.
Examples include aromatic hydrocarbons such as benzene, toluene, chlorobenzene, and dichlorobenzene, and halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, and ethylene chloride. Note that the solvent is preferably sufficiently dehydrated prior to the reaction. There are no particular restrictions on the order of addition of raw materials, but
It is convenient to add a solution of phosgene or chloroformic acid trichloromethyl ester in an organic solvent to a solution or suspension containing the aminomaleimide and pyridine in an organic solvent. The amount of aminomaleimides to be used is preferably 0.4 to 1 mol per mol of phosgene and 0.2 to 0.5 mol per mol of chloroformic acid trichloromethyl ester, and in order to obtain the target product with a good yield, it is 0.4 to 1 mol per mol of phosgene. ~0.5 mol, particularly preferably 0.2 to 0.25 mol per mole of chloroformic acid trichloromethyl ester. The amount of pyridine used is approximately 2 per mole of phosgene.
mole, preferably about 4 moles per mole of chloroformic acid trichloromethyl ester. If the reaction temperature is too high, the yield of the desired product will decrease, so it is generally preferable to employ a temperature in the range of -20 to 100°C. Reaction time is usually 1~
It is 30 hours. The desired product, pyrrolopyrimidine, can be isolated, for example, by the following method. After washing the reaction product mixture with water to remove by-product pyridinium chloride as an aqueous solution, the organic solvent is distilled off to obtain a mixture containing the desired product, which is then subjected to a conventional purification method such as recrystallization. Thus, the purified product of interest is isolated. Specific examples of pyrrolopyrimidines represented by the formula [] obtained in this invention include 3,6-dimethyl-2-hydroxy-3,4,6,7-tetrahydro-4,5,7-trioxo-5H- Pyrrolo[3,4-d]pyrimidine, 3,6-diethyl-
2-Hydroxy-3,4,6,7-tetrahydro-4,5,7-trioxo-5H-pyrrolo[3,
4-d]pyrimidine, 3,6-dipropyl-2-
Hydroxy-3,4,6,7-tetrahydro-
4,5,7-trioxo-5H-pyrrolo[3,4
-d] Pyrimidine, 3,6-dibutyl-2-hydroxy-3,4,6,7-tetrahydro-4,
5,7-trioxo-5H-pyrrolo [3,4-d]
Pyrimidine, 3,6-diallyl-2-hydroxy-3,4,6,7-tetrahydro-4,5,7-
Trioxo-5H-pyrrolo[3,4-d]pyrimidine, 3,6-dicyclohexyl-2-hydroxy-3,4,6,7-tetrahydro-4,5,7
-trioxo-5H-pyrrolo[3,4-d]pyrimidine, 3,6-dibenzyl-2-hydroxy-
3,4,6,7-tetrahydro-4,5,7-trioxo-5H-pyrrolo[3,4-d]pyrimidine, 3,6-diphenyl-2-hydroxy-3,
4,6,7-tetrahydro-4,5,7-trioxo-5H-pyrrolo[3,4-d]pyrimidine,
3,6-bis(chlorophenyl)-2-hydroxy-3,4,6,7-tetrahydro-4,5,7
-trioxo-5H-pyrrolo[3,4-d]pyrimidine, 3,6-bis(dichlorophenyl)-2
-Hydroxy-3,4,6,7-tetrahydro-
4,5,7-trioxo-5H-pyrrolo[3,4
-d] Pyrimidine, etc. Next, examples will be shown. In the Examples, the yield of pyrrolopyrimidine is the yield based on the aminomaleimide used. Example 1 To 20 ml of ethylene chloride containing 0.92 g of 3-amino-1-methyl-4-(methylcarbamoyl)maleimide and 1.71 g of pyridine, 1.07 g of trichloromethyl chloroformate was added under cooling with a cryogen (ice-salt).
After adding dropwise 20 ml of ethylene chloride containing 20 ml of ethylene chloride, the mixture was allowed to react for 1 day with stirring at room temperature. After the reaction, 50 ml of water was added to the resulting reaction product mixture and filtered to give 3,6-dimethyl-2-hydroxy-3,4,6,7-tetrahydro-4,5,7-
0.49 g (47% yield, same hereinafter) of crystals of trioxo-5H-pyrrolo[3,4-d]pyrimidine was obtained. This was recrystallized with ethanol and the decomposition point was 291.
Orange needle-shaped crystals were obtained at ~292°C. The elemental analysis values are shown below. C H N Analytical value 45.98 3.40 19.87 Calculated value 45.94 3.38 20.09 (as C ₈ H ₇ N ₃ O ₄ ) Example 2 1-allyl-3-(allylcarbamoyl)-4
- Add 20 ml of ethylene chloride containing 1.18 g of aminomaleimide and 1.7 g of pyridine under cooling with a cryogen (ice-salt).
After 20 ml of ethylene chloride containing 1.07 g of chloroformic acid trichloromethyl ester was added dropwise, the mixture was allowed to react for 5 hours while being stirred and cooled with a cryogen (ice-salt). After the reaction, the resulting reaction product mixture was mixed with a cryogen (ice-
Salt) While cooling, 50 ml of water was added to separate into an aqueous layer and an organic layer. After drying the organic layer over anhydrous sodium sulfate, the resulting residue was concentrated under reduced pressure and passed through a column (diameter 30 mm) packed with silica gel (Wako Gel C-200, 200 g) to determine the volume ratio of ethylene chloride and ethanol. Elution was performed with a 9:1 mixed solvent. solvent
The solution obtained by elution with 320 ml was concentrated under reduced pressure.
20 ml of benzene was added to the residue and filtered to obtain 3,6-diallyl-2-hydroxy-3,4,6,7-tetrahydro-4,5,7-trioxo-5H-pyrrolo[3,4-d]pyrimidine. Crystal 0.86g (66
%) was obtained. This was recrystallized from benzene to give a melting point of
Pale yellow fine needle crystals at 193-194°C were obtained. The elemental analysis values are shown below. C H N Analytical value 55.05 4.20 16.32 Calculated value 55.17 4.25 16.08 (as C ₁₂ H ₁₁ N ₃ O ₄ ) Example 3 1.68 g of 3-amino-1-benzyl-4-(benzylcarbamoyl)maleimide and 1.68 g of pyridine
To 20ml of ethylene chloride containing chloroformate trichloromethyl ester under cooling with a cryogen (ice-salt)
After dropping 20 ml of ethylene chloride containing g, the mixture was reacted for 20 hours with stirring at room temperature. After the reaction, 50 ml of water was added to the resulting reaction product mixture to separate it into an aqueous layer and an organic layer. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
The mixture was passed through a column (diameter 30 mm) packed with 200 g) and eluted with a mixed solvent of ethylene chloride and ethyl acetate in a volume ratio of 7:3. First, after elution with 240 ml of solvent,
The solution obtained by elution with 200 ml of solvent was concentrated under reduced pressure. Add 20 ml of benzene to the residue and filter it.
-dibenzyl-2-hydroxy-3,4,6,7
-Tetrahydro-4,5,7-trioxo-5H
-Pyrrolo[3,4-d]pyrimidine crystals 1.59g
(88%). This was recrystallized from ethyl acetate,
Pale yellow crystals with a melting point of 224-225°C were obtained. The elemental analysis values are shown below. C H N Analytical value 66.67 4.16 11.72 Calculated value 66.48 4.18 11.63 (as C ₂₀ H ₁₅ N ₃ O ₄ ) Example 4 3.07 g of 3-amino-1-phenyl-4-(phenylcarbamoyl)maleimide and 1.94 g of pyridine
20 ml of ethylene chloride containing 1.21 g of phosgene was added dropwise to 40 ml of ethylene chloride containing 1.21 g of phosgene under cooling with a cryogen (ice-salt), and the mixture was heated and reacted under reflux for 30 minutes. After the reaction, the resulting reaction product mixture was added with water at room temperature.
25 ml was added and filtered to recover 0.55 g of raw aminomaleimide crystals. The liquid was separated into an aqueous layer and an organic layer. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was recrystallized with 50 ml of ethanol to give 3,6-diphenyl-2-hydroxy-3, 3,6-diphenyl-2-hydroxy-3,
0.59 g (16
%) was obtained. The elemental analysis values are shown below. C H N Analytical value 63.35 4.36 11.30 Calculated value 63.32 4.52 11.08 (as C ₂₀ H ₁₇ N ₃ O ₅ ) Example 5 1.54 g of 3-amino-1-phenyl-4-(phenylcarbamoyl)maleimide and 1.68 g of pyridine
To 20 ml of ethylene chloride containing chloroformate trichloromethyl ester under cooling with a cryogen (ice-salt)
After dropping 20 ml of ethylene chloride containing g, the mixture was reacted for 16 hours with stirring at room temperature. After the reaction, the resulting reaction product mixture was added with water at room temperature.
50 ml was added to separate into an aqueous layer and an organic layer. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. 50 ml of ethanol was added to the resulting residue, filtered, and 3,6-diphenyl-2-hydroxy-3,
1.41 g (84%) of crystals of 4,6,7-tetrahydro-4,5,7-trioxo-5H-pyrrolo[3,4-d]pyrimidine were obtained. Example 6 3-amino-1-(P-tolyl)-4-(P-
40 ml of ethylene chloride containing 3.35 g of maleimide (tolylcarbamoyl) and 1.94 g of pyridine,
After cooling, 20 ml of ethylene chloride containing 1.21 g of phosgene was added dropwise, and the mixture was allowed to react for one day while stirring at room temperature. After the reaction, the resulting reaction product mixture was added with water at room temperature.
25 ml was added and filtered to recover 0.93 g of raw aminomaleimide crystals. The liquid was separated into an aqueous layer and an organic layer. After drying the organic layer over anhydrous sodium sulfate, 25% of benzene was added to the residue obtained by concentrating the organic layer under reduced pressure.
ml of ethylene chloride and filtrate the mixture.
After washing with 30 ml, 0.65 g of raw material aminomaleimide crystals were recovered. The liquid and washings were combined and concentrated under reduced pressure. The residue was transferred to a column (diameter
25 mm) and eluted with a mixed solvent of benzene and ethyl acetate. First, 500 ml of mixed solvent with a volume ratio of 9:1
ml, then eluted with 150 ml of a mixed solvent with a volume ratio of 4:1, and then eluted with 300 ml of a mixed solvent with a volume ratio of 4:1. The obtained solution was concentrated under reduced pressure to obtain 3,6-di(P
-tolyl)-2-hydroxy-3,4,6,7-
Tetrahydro-4,5,7-trioxo-5H-
Pyrrolo[3,4-d]pyrimidine crystals 0.34g
(9%) was obtained. This was recrystallized with ethanol,
Yellow microneedle crystals with a decomposition point of 276-77°C were obtained. The elemental analysis values are shown below. C H N Analytical value 66.25 4.19 11.79 Calculated value 66.48 4.18 11.63 (as C ₂₀ H ₁₅ N ₃ O ₄ ) Example 7 3-Amino-1-(2,4-dichlorophenyl)-4-(2,4- Add 20 ml of ethylene chloride containing 2.23 g of dichlorophenylcarbamoyl (dichlorophenylcarbamoyl)maleimide and 1.7 g of pyridine under cooling with a cryogen (ice-salt).
After 20 ml of ethylene chloride containing 1.06 g of trichloromethyl chloroformate was added dropwise, the mixture was reacted for 20 hours with stirring under cooling with a cryogen (ice-salt). After the reaction, 50 ml of water was added to the resulting reaction mixture while cooling with a cryogen (ice-salt) to separate the mixture into an aqueous layer and an organic layer. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. Ethylene chloride residue
Recrystallize with 30 ml to obtain 3,6-bis(2,4-dichlorophenyl)-2-hydroxy-3,4,6,
7-tetrahydro-4,5,7-trioxo-
0.7 g (30%, decomposition point 262-264°C) of pale yellow needle crystals of 5H-pyrrolo[3,4-d]pyrimidine was obtained. The elemental analysis values are shown below. C H N Cl Analytical value 45.93 1.78 8.67 29.99 Calculated value 45.89 1.50 8.92 30.10 (as C ₁₈ H ₇ Cl ₄ N ₃ O ₄ ) Example 8 2.72 g of 3-amino-1-cyclohexyl-4-(cyclohexylcarbamoyl)maleimide 20 ml of ethylene chloride containing 2.27 g of chloroformic acid trichloromethyl ester was added dropwise to 70 ml of ethylene chloride containing 3.37 g of pyridine under cooling with a cryogen (ice-salt), and the mixture was allowed to react for one day while stirring at room temperature. After the reaction, the resulting reaction product mixture was added with water at room temperature.
Add 50 ml and filter, 3,6-dicyclohexyl-2-hydroxy-3,4,6,7-tetrahydro-4,5,7-trioxo-5H-pyrrolo[3,
4-d] 1.35 g (46%) of pyrimidine crystals were obtained. The liquid was separated into an aqueous layer and an organic layer, and the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was recrystallized from dioxane to further obtain the target pyrropyrimidine as an adduct with dioxane (molar ratio 2:1). Yield 0.51g (15%).
Decomposition point: 90℃. The elemental analysis values are shown below. C H N Analysis value 61.84 7.22 11.19 Calculated value 61.68 6.99 10.79 (as C ₁₈ H ₂₃ N ₃ O ₄・1/2C ₄ H ₈ O ₂ )

Claims (1)

[Claims] 1 formula [In the formula, R ¹ is an alkyl group having 1 to 4 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, a cycloalkyl group having 5 to 7 carbon atoms, an aralkyl group having 7 to 10 carbon atoms, or [Formula] (R ² represents an alkyl group having 1 to 4 carbon atoms or a halogen atom, and n is 0, 1, 2
Or 3. ) represents a group. ] is characterized by reacting an aminomaleimide represented by the formula with phosgene or chloroformic acid trichloromethyl ester in the presence of pyridine. (In the formula, R ¹ has the same meaning as above.) A method for producing pyrrolopyrimidines represented by the formula: