JPH0216313B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing imidazopyrimidines, which are new compounds. More specifically, the invention provides the formula [In the formula, R ¹ is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a phenyl group, an alkoxycarbonyl group having 2 to 5 carbon atoms, an aliphatic acyl group having 2 to 5 carbon atoms, a benzoyl group, a cyano group, or a halogen group. Indicates an atom, ^R2 is a hydrogen atom, an alkyl group having 1 to 10 carbon atoms,
Allyl group, cyclohexyl group, benzyl group, or

[Formula] (R ⁴ represents an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, or a halogen atom, and n is 0.1 or 2), and R ³ is a carbon It represents an alkyl group of numbers 1 to 4. ] Orotate ester represented by the formula R ⁵ -N=C=O [] [wherein R ⁵ is an alkyl group having 1 to 10 carbon atoms, an allyl group, a cyclohexyl group, a benzyl group, or

[Formula] (R ⁴ and n each have the same meanings as above). ] isocyanate represented by
characterized in that the reaction is carried out in the presence of an amine and/or a quaternary ammonium fluoride. This is a method for producing imidazopyrimidines represented by the formula (wherein R ¹ , R ² and R ⁵ each have the same meanings as above). The imidazopyrimidines obtained by this invention are
It is useful as agricultural chemicals, medicines, and intermediates thereof. It is particularly useful as an agricultural and horticultural fungicide against rice leaf blight. Specific examples of orotate esters represented by formula [] include ethyl orotate, ethyl 1-phenyl orotate, ethyl 5-methyl orotate, ethyl 5-methyl-1-phenyl orotate, and 1-butyl-5-phenyl orotate. Ethyl, ethyl 5-(ethoxycarbonyl)orotate, ethyl 5-ethoxycarbonyl-1-propylorotate, ethyl 1-butyl-5-(ethoxycarbonyl)orotate, 1-cyclohexyl-5-(ethoxycarbonyl)orotate Ethyl, ethyl 5-ethoxycarbonyl-1-phenylorotate, ethyl 5-ethoxycarbonyl-1-tolyrotate, ethyl 5-ethoxycarbonyl-1-(methoxyphenyl)orotate,
Ethyl 1-dichlorophenyl-5-(ethoxycarbonyl)orotate, ethyl 5-acetyl-1-ethyl orotate, ethyl 5-acetyl-1-cyclohexyl orotate, 5-acetyl-1-
Ethyl tolyrotate, 5-acetyl-1-
(methoxyphenyl)ethyl orotate, ethyl 5-acetyl-1-chlorophenyl orotate,
Ethyl 5-benzoyl-1-ethylorotate,
Ethyl 5-benzoyl-1-butylorotate,
Ethyl 5-benzoyl-1-cyclohexylorotate, ethyl 5-benzoyl-1-phenylorotate, ethyl 5-benzoyl-1-(methoxyphenyl)orotate, 5-benzoyl-1-
Ethyl dichlorophenyl orotate, ethyl 5-cyano-1-ethyl orotate, 1-butyl-5
-Ethyl cyanoorotate, ethyl 5-cyano-1-cyclohexylorotate, 1-allyl-5
-Ethyl cyanoorotate, 1-benzyl-5-
Ethyl cyanoorotate, ethyl 5-cyano-1-phenylorotate, ethyl 5-fluoroorotate, ethyl 5-fluoro-1-methylorotate, ethyl 1-allyl-5-fluoroorotate, 1-benzyl-5-fluoro Examples include ethyl orotate, ethyl 5-fluoro-1-phenyl orotate, ethyl 5-chloroorotate, ethyl 5-bromoorotate, ethyl 5-bromo-1-propylorotate, ethyl 5-bromo-1-phenyl orotate, etc. It will be done. Specific examples of the isocyanate represented by the formula [] include methyl isocyanate, ethyl isocyanate, propyl isocyanate, butyl isocyanate, hexyl isocyanate, allyl isocyanate, cyclohexyl isocyanate,
Benzyl isocyanate, phenyl isocyanate, tolyl isocyanate, methoxyphenyl isocyanate, chlorophenyl isocyanate,
Examples include dichlorophenyl isocyanate. Specific examples of the tertiary amine include aliphatic tertiary amines such as trimethylamine, triethylamine, tripropylamine, and tributylamine. Quaternary ammonium fluoride has the formula [In the formula, R ⁶ , R ⁷ , R ⁸ and R ⁹ each represent an alkyl group having 1 to 4 carbon atoms or a benzyl group. ), and specific examples thereof include benzyltrimethylammonium fluoride, methyltributylammonium fluoride, tetraethylammonium fluoride, tetrabutylammonium fluoride, and tetramethylammonium fluoride. The reaction is carried out in an inert organic solvent such as benzene,
Aromatic hydrocarbons such as toluene, chlorobenzene, dichlorobenzene, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, ethylene chloride, acetonitrile, propionitrile,
It is carried out in the presence of nitriles such as benzonitrile. However, when the substituent R ² is a hydrogen atom in the orotate ester represented by the formula It is not preferred because it may be alkylated. As a reaction method, under substantially anhydrous conditions,
Orotic acid esters, isocyanates and tertiary
Any method of contacting the amine and/or quaternary ammonium fluoride can be employed,
There is no particular restriction on the order of these additions. The amount of isocyanate used is preferably 2 moles or more per mole of orotate ester. The amounts of the tertiary amine and quaternary ammonium fluoride used are preferably 1 to 3 mol and 0.1 to 1 mol, respectively, per mol of orotate ester. In this reaction, the tertiary amine and quaternary ammonium fluoride have the effect of promoting the reaction. When aromatic isocyanates are used, tertiary amines and quaternary ammonium fluorides are usually used alone, but when using aliphatic isocyanates with low reactivity, they are used to speed up the reaction. It is preferred to use a combination of tertiary amine and quaternary ammonium fluoride. The reaction is generally carried out at a temperature ranging from 20 to 150°C.
It lasts from 1 to 50 hours. Specific examples of imidazopyrimidines represented by the formula [] and their melting points are shown below.

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[Table] Examples are shown below. Example 1 (Compound No. 1) Tetraethylammonium fluoride dihydrate
130 ml of ethylene chloride containing 2.89 g was heated and 80 ml of the solvent was distilled off under normal pressure to remove water from the mixture. After cooling, add triethylamine to the mixture at room temperature.
70 ml of benzene containing 1.52 g was added dropwise, followed by 2.76 g of ethyl orotate, followed by benzene containing 3.76 g of cyclohexyl isocyanate.
20ml was added dropwise. The mixture was heated and reacted under reflux for 14 hours. After the reaction, the resulting reaction product mixture is filtered,
The liquid was concentrated under reduced pressure. Add 50ml of benzene and water to the residue.
Add 50ml and filter, 2-cyclohexyl-1,
2,3,5,6,7-hexahydro-1,3,
1.47 g of crystals of 5,7-tetraoxoimidazo[1,5-C]pyrimidine were obtained. This was recrystallized from ethylene chloride to obtain colorless crystals with a melting point of 269-271°C. The elemental analysis values are shown below. C H N Analytical value 54.67 5.00 16.09 Calculated value 54.75 4.98 15.96 (as C ₁₂ H ₁₃ N ₃ O ₄ ) Example 2 (Compound No. 2) 2.82 g of ethyl orotate and triethylamine
In 120 ml of ethylene chloride containing 1.55 g, ethylene chloride 30 containing 3.65 g of phenyl isocyanate at room temperature
ml was added dropwise. The mixture was heated and reacted under reflux for 4 hours. After the reaction, the resulting reaction product mixture is filtered,
2.59 g of crystals of 2-phenyl-1,2,3,5,6,7-hexahydro-1,3,5,7-tetraoxoimidazo[1,5-C]pyrimidine were obtained.
This was recrystallized with acetonitrile and the decomposition point was 288.
Colorless petal-like crystals at ~290°C were obtained. The elemental analysis values are shown below. C H N Analytical value 56.18 2.80 16.56 Calculated value 56.04 2.74 16.34 (as C ₁₂ H ₇ N ₃ O ₄ ) Example 3 (Compound No. 4) In 30 ml of ethylene chloride containing 1.65 g of ethyl 1-phenyl orotate and 0.64 g of triethylamine, 20 ml of ethylene chloride containing 1.51 g of phenyl isocyanate were added dropwise at room temperature. The mixture was heated and reacted under reflux for 3.5 hours. After the reaction, the resulting reaction product mixture is filtered,
2,6-diphenyl-1,2,3,5,6,7-
1.21 g of crystals of hexahydro-1,3,5,7-tetraoxoimidazo[1,5-C]pyrimidine were obtained. This was recrystallized from isopropyl alcohol to obtain colorless needle crystals with a melting point of 274°C. The elemental analysis values are shown below. C H N Analytical value 64.83 3.30 12.50 Calculated value 64.87 3.33 12.61 (as C ₁₈ H ₁₁ N ₃ O ₄ ) Example 4 (Compound No. 5) In 20 ml of ethylene chloride containing 0.43 g of ethyl 5-methylorotate and 0.22 g of triethylamine , 10 ml of ethylene chloride containing 0.52 g of phenyl isocyanate was added dropwise at room temperature. Heat the mixture and
The reaction was carried out under reflux for 3 hours. After the reaction, the resulting reaction product mixture was concentrated under reduced pressure. 10 ml of ethylene chloride was added to the residue and filtered to give 8-methyl-2-phenyl-1,2,3,
0.19 g of crystals of 5,6,7-hexahydro-1,3,5,7-tetraoxoimidazo[1,5-C]pyrimidine were obtained. This was recrystallized from chlorobenzene to obtain colorless needle crystals with a decomposition point of 287-289°C. The elemental analysis values are shown below. C H N Analytical value 57.81 3.52 15.37 Calculated value 57.57 3.34 15.49 (as C ₁₃ H ₉ N ₃ O ₄ ) Example 5 (Compound No. 6) Ethyl 5-methyl-1-phenyl orotate
Add p-tolylisocyanate to 30 ml of ethylene chloride containing 1.34 g of triethylamine and 0.49 g of triethylamine at room temperature.
20 ml of ethylene chloride containing 1.30 g was added dropwise.
The mixture was heated and reacted under reflux for 6.5 hours. After the reaction, the resulting reaction product mixture is filtered,
The liquid was concentrated under reduced pressure, and 50 ml of isopropyl alcohol was added to the residue, which was filtered to give 8-methyl-6-phenyl-2-(p-tolyl)-1,2,3,5,
Crystals of 6,7-hexahydro-1,3,5,7-tetraoxoimidazo[1,5-C]pyrimidine
0.50g was obtained. This was recrystallized from isopropyl alcohol to obtain colorless crystals with a melting point of 246°C. The elemental analysis values are shown below. C H N Analytical value 66.40 4.15 11.39 Calculated value 66.48 4.18 11.63 (as C ₂₀ H ₁₅ N ₃ O ₄ ) Example 6 (Compound No. 7) 1.67 g of ethyl 1-(n-butyl)-5-phenyl orotate and 0.53 g of triethylamine 20 ml of ethylene chloride containing 1.40 g of p-tolylisocyanate was added dropwise at room temperature. The mixture was allowed to react for 2 days with stirring at room temperature. After the reaction, the resulting reaction product mixture is filtered,
The liquid was concentrated under reduced pressure. The residue was transferred to a column (diameter
25 mm) and eluted with benzene. benzene
After elution with 1800 ml, the solution obtained by elution with 2500 ml of benzene was concentrated under reduced pressure to obtain 6-(n-butyl).
-8-phenyl-2-(p-tolyl)-1,2,
3,5,6,7-hexahydro-1,3,5,7
-2.00 g of crystals of tetraoxoimidazo[1,5-C]pyrimidine were obtained. This was recrystallized from isopropyl alcohol to obtain colorless microacicular crystals with a melting point of 158-160°C. The elemental analysis values are shown below. C H N Analytical value 68.38 5.26 10.39 Calculated value 68.47 5.25 10.42 (as C ₂₃ H ₂₁ N ₃ O ₄ ) Example 7 (Compound No. 8) Ethyl 5-(ethoxycarbonyl)orotate
Benzene containing 0.59g and triethylamine 0.47g
10 ml of benzene containing 0.82 g of phenyl isocyanate was added dropwise to 20 ml at room temperature. The mixture was heated and reacted under reflux for 7 hours. After the reaction, the resulting reaction product mixture is filtered,
The liquid was concentrated under reduced pressure. The residue was filtered with 5 ml of ethanol, and 8-ethoxycarbonyl-2-phenyl-1,2,3,5,6,7-hexahydro-1,3,5,7-tetraoxoimidazo[1,
0.33 g of crystals of 5-C]pyrimidine were obtained. This was recrystallized from acetonitrile to obtain colorless crystals with a decomposition point of 288°C. The elemental analysis values are shown below. C H N Analytical value 54.29 3.36 12.53 Calculated value 54.72 3.37 12.76 (as C ₁₅ H ₁₁ N ₃ O ₆ ) Example 8 (Compound No. 9) 1.07 g of ethyl 5-ethoxycarbonyl-1-isopropylorotate and 0.49 g of triethylamine
10 ml of benzene containing 1.07 g of phenyl isocyanate was added dropwise at room temperature to 20 ml of benzene containing phenyl isocyanate. The mixture was heated and reacted under reflux for 5 hours. After the reaction, the resulting reaction product mixture was concentrated under reduced pressure. 20 ml of isopropyl ether was added to the residue and filtered to give 8-ethoxycarbonyl-6-isopropyl-2-phenyl-1,2,3,5,6,7.
-Hexahydro-1,3,5,7-tetraoxoimidazo[1,5-C]pyrimidine crystals 1.18g
I got it. This was recrystallized with carbon tetrachloride to obtain a melting point of
Colorless crystals were obtained at 186-188°C. The elemental analysis values are shown below. C H N Analyzed value 57.56 4.64 11.35 Calculated value 58.22 4.61 11.32 (as C ₁₈ H ₁₇ N ₃ O ₆ ) Example 9 (Compound No. 12) Ethylene chloride containing 1.51 mmol of tetraethylammonium fluoride and 0.31 g of nitriethylamine
To 14 ml was added 0.51 g of ethyl 1-cyclohexyl-5-(ethoxycarbonyl)orotate at room temperature, and then 20 ml of ethylene chloride containing 0.17 g of methyl isocyanate was added dropwise. The mixture was heated and reacted under reflux for 8.5 hours. After the reaction, the resulting reaction product mixture was concentrated under reduced pressure. 30 ml of ethylene chloride and 20 ml of water were added to the residue, and the layers were separated into an organic layer and an aqueous layer. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure.
Add 10 ml of isopropyl ether to the residue and
Cyclohexyl-8-ethoxycarbonyl-2-
Methyl-1,2,3,5,6,7-hexahydro-1,3,5,7-tetraoxoimidazo[1,
0.40 g of crystals of 5-C]pyrimidine were obtained. This was recrystallized from ethylene chloride to obtain colorless needle crystals with a melting point of 256°C. The elemental analysis values are shown below. C H N Analyzed value 55.23 5.40 11.94 Calculated value 55.01 5.42 12.03 (as C ₁₆ H ₁₉ N ₃ O ₆ ) Example 10 (Compound No. 15) Ethylene chloride 30 containing 0.83 g of triethylamine
ml of ethyl 5-ethoxycarbonyl-1-phenylorotate at room temperature, and then 10 ml of ethylene chloride containing 0.98 g of phenyl isocyanate.
ml was added dropwise. The mixture was heated and reacted under reflux for 2 hours. After the reaction, the resulting reaction product mixture is filtered,
2,6-diphenyl-8-ethoxycarbonyl-
1,2,3,5,6,7-hexahydro-1,
3,5,7-tetraoxoimidazo[1,5-
C] 0.87 g of pyrimidine crystals were obtained. This was recrystallized from toluene to obtain colorless needle crystals with a melting point of 336-338°C. The elemental analysis values are shown below. C H N Analytical value 62.49 3.88 10.15 Calculated value 62.22 3.73 10.37 (as C ₂₁ H ₁₅ N ₃ O ₆ ) Example 11 (Compound No. 16) Ethylene chloride containing 2.75 mmol of tetraethylammonium fluoride and 0.56 g of triethylamine
Add 5-ethoxycarbonyl-1- to 17 ml at room temperature.
(p-methoxyphenyl)ethyl orotate 1.00
g and then 20 ml of ethylene chloride containing 0.39 g of ethyl isocyanate was added dropwise. The mixture was heated and reacted under reflux for 7.5 hours. After the reaction, the resulting reaction product mixture was concentrated under reduced pressure. 20 ml of chloroform and 30 ml of water were added to the residue, and the layers were separated into an organic layer and an aqueous layer. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. 5 ml of toluene was added to the residue and filtered to give 8-ethoxycarbonyl-2-ethyl-6-(p-methoxyphenyl)-1,2,3,5,6,7-hexahydro-1,3,5,7. -0.36 g of crystals of tetraoxoimidazo[1,5-C]pyrimidine were obtained. This is recrystallized from benzene and has a melting point of 239-240.
C. colorless needle crystals were obtained. The elemental analysis values are shown below. C H N Analytical value 56.07 4.41 10.63 Calculated value 55.81 4.42 10.85 (as C ₁₈ H ₁₇ N ₃ O ₇ ) Example 12 (Compound No. 20) In 40 ml of ethylene chloride containing 3.13 mmol of tetraethylammonium fluoride and 0.55 g of triethylamine, 1-(p-chlorophenyl)- at room temperature
Ethyl 5-(ethoxycarbonyl)orotate
Add 1.00g, then n-butyl isocyanate
10 ml of ethylene chloride containing 0.54 g was added dropwise. The mixture was heated and reacted under reflux for 12.5 hours. After the reaction, the resulting reaction product mixture was washed with 50 ml of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Add 50 ml of isopropyl ether to the residue, and add 2-(n-butyl)-6-(p-chlorophenyl)-8-ethoxycarbonyl-1,2,3,
0.31 g of crystals of 5,6,7-hexahydro-1,3,5,7-tetraoxoimidazo[1,5-C]pyrimidine was obtained. This was recrystallized from benzene to obtain colorless needle crystals with a melting point of 247-250°C. The elemental analysis values are shown below. C H N Analytical value 54.72 4.38 10.01 Calculated value 54.36 4.32 10.00 (as C ₁₉ H ₁₈ ClN ₃ O ₆ ) Example 13 (Compound No. 22) Ethyl 5-acetyl-1-ethylorotate
To 20 ml of ethylene chloride containing 0.76 g, 5 ml of ethylene chloride containing 0.60 g of triethylamine is added dropwise at room temperature, followed by 1.00 g of p-tolylisocyanate.
10 ml of ethylene chloride containing g was added dropwise. The mixture was heated and reacted under reflux for 18 hours. After the reaction, the resulting reaction product mixture was concentrated under reduced pressure. 15 ml of benzene and 15 ml of water were added to the residue, filtered, and 8-acetyl-6-ethyl-2-(p-tolyl)-1,2,3,5,6,7-hexahydro-
1,3,5,7-tetraoxoimidazo[1,5
-C] 0.27 g of pyrimidine crystals were obtained. This was recrystallized from ethylene chloride to obtain pale yellow crystals with a decomposition point of 270-273°C. The elemental analysis values are shown below. C H N Analytical value 59.79 4.70 12.16 Calculated value 59.82 4.43 12.31 (as C ₁₇ H ₁₅ N ₃ O ₅ ) Example 14 (Compound No. 23) In 20 ml of benzene containing 1.00 g of ethyl 5-acetyl-1-cyclohexyl orotate, 5 ml of benzene containing 0.66 g of triethylamine is added dropwise at room temperature, followed by 1.08 g of p-tolylisocyanate.
10 ml of benzene containing was added dropwise. The mixture was heated and reacted under reflux for 15 hours. After the reaction, the resulting reaction product mixture was concentrated under reduced pressure. 20 ml of isopropyl alcohol was added to the residue and filtered to give 8-acetyl-6-cyclohexyl-2-(p-tolyl)-1,2,3,5,6,7.
-Hexahydro-1,3,5,7-tetraoxoimidazo[1,5-C]pyrimidine crystals 1.08g
I got it. This was recrystallized from acetonitrile to obtain colorless crystals with a decomposition point of 290-292°C. The elemental analysis values are shown below. C H N Analytical value 63.92 5.38 10.90 Calculated value 63.79 5.35 10.63 (as C ₂₁ H ₂₁ N ₃ O ₅ ) Example 15 (Compound No. 25) Contains 1.00 g of ethyl 5-acetyl-1-(p-tolyl) orotate To 15 ml of benzene, 4 ml of ethylene chloride containing 1.54 mmol of tetraethylammonium fluoride, 5 ml of benzene containing 0.64 g of triethylamine, and 10 ml of benzene containing 1.07 g of p-chlorophenyl isocyanate were added dropwise in this order at room temperature. The mixture was heated and reacted under reflux for 17.5 hours. After the reaction, the resulting reaction product mixture is filtered,
8-acetyl-2-(p-chlorophenyl)-6
0.41 g of crystals of -(p-tolyl)-1,2,3,5,6,7-hexahydro-1,3,5,7-tetraoxoimidazo[1,5-C]pyrimidine were obtained. This was recrystallized with acetonitrile to obtain the decomposition point.
Colorless crystals were obtained at 343°C. The elemental analysis values are shown below. C H N Cl Analytical value 59.49 3.51 9.54 8.40 Calculated value 59.51 3.33 9.91 8.37 (as C ₂₁ H ₁₄ ClN ₃ O ₅ ) Example 16 (Compound No. 26) 5-acetyl-1-(p-methoxyphenyl)
20 ml of ethylene chloride containing 0.85 g of ethyl orotate
5 ml of ethylene chloride containing 0.52 g of triethylamine was added dropwise at room temperature, followed by 10 ml of ethylene chloride containing 0.95 g of p-methoxyphenyl isocyanate. The mixture was heated and reacted under reflux for 14.5 hours. After the reaction, the resulting reaction product mixture was filtered and
-Acetyl-2,6-di(p-methoxyphenyl)-1,2,3,5,6,7-hexahydro-
1,3,5,7-tetraoxoimidazo[1,5
-C] 0.61 g of pyrimidine crystals were obtained. This was recrystallized from acetonitrile to obtain pale yellow needle crystals with a decomposition point of 325°C. The elemental analysis values are shown below. C H N Analytical value 60.77 4.02 9.37 Calculated value 60.69 3.94 9.65 (as C ₂₂ H ₁₇ N ₃ O ₇ ) Example 17 (Compound No. 27) Contains 1.00 g of ethyl 5-acetyl-1-(p-chlorophenyl) orotate Benzene 5 containing 0.60 g of triethylamine in 20 ml of benzene at room temperature
ml, 10 ml of benzene containing 1.14 g of p-chlorophenyl isocyanate, and ethylene chloride containing 1.54 mmol of tetraethylammonium fluoride 4
ml were added dropwise in this order. Heat the mixture;
The reaction was carried out under reflux for 3.5 hours. After the reaction, the reaction product mixture obtained was filtered and water was added.
Wash with 20ml and add 8-acetyl-2,6-di(p-
0.76 g of crystals of chlorophenyl)-1,2,3,5,6,7-hexahydro-1,3,5,7-tetraoxoimidazo[1,5-C]pyrimidine were obtained. This was recrystallized from dimethyl sulfoxide and
Colorless crystals with a decomposition point of 365°C were obtained. The elemental analysis values are shown below. C H N Cl Analytical value 53.61 2.66 9.15 15.60 Calculated value 54.07 2.50 9.46 15.96 (as C ₂₀ H ₁₁ Cl ₂ N ₃ O ₅ ) Example 18 (Compound No. 30) 5-benzoyl-1-(n-butyl)orotic acid In 15 ml of benzene containing 1.00 g of ethyl, 7.5 ml of ethylene chloride containing 2.95 mmol of tetraethylammonium fluoride and 0.59 triethylamine at room temperature.
5 ml of benzene containing g and 7.5 ml of benzene containing 0.91 g of cyclohexyl isocyanate were added dropwise in this order. The mixture was heated and reacted under reflux for 8 hours. After the reaction, the resulting reaction product mixture was washed with 30 ml of water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Add 20 ml of isopropyl ether to the residue and add 8-benzoyl-6-(n-butyl)-2.
0.91 g of crystals of -cyclohexyl-1,2,3,5,6,7-hexahydro-1,3,5,7-tetraoxoimidazo[1,5-C]pyrimidine were obtained. This is recrystallized with benzene, and the decomposition point is 246 ~
Colorless crystals were obtained at 248°C. The elemental analysis values are shown below. C H N Analytical value 65.03 6.02 9.92 Calculated value 65.24 5.95 9.92 (as C ₂₃ H ₂₅ N ₃ O ₅ ) Example 19 (Compound No. 32) In 30 ml of ethylene chloride containing 2.00 g of ethyl 5-benzoyl-1-cyclohexyl orotinate , 12.5 ml of ethylene chloride containing 4.92 g mmol of tetraethylammonium fluoride at room temperature, 10 ml of ethylene chloride containing 1.09 g of triethylamine, and 15 ml of ethylene chloride containing 1.49 g of cyclohexyl isocyanate were added dropwise in this order. The mixture was heated and reacted under reflux for 3 hours. After the reaction, 5 ml of ethanol was added to the resulting reaction product mixture at room temperature and filtered. The liquid was concentrated under reduced pressure, and 15 ml of ethanol was added to the residue, which was filtered to give 8-benzoyl-2,6-dicyclohexyl-1,2,3,5,6,7-hexahydro-1,
3,5,7-tetraoxoimidazo[1,5-
C] 0.98 g of pyrimidine crystals were obtained. This is 1,
Recrystallized with 4-dioxane, decomposition point 332-334℃
Colorless crystals were obtained. The elemental analysis values are shown below. C H N Analytical value 66.92 6.02 9.51 Calculated value 66.80 6.05 9.35 (as C ₂₅ H ₂₇ N ₃ O ₅ ) Example 20 (Compound No. 33) In 20 ml of ethylene chloride containing 1.00 g of ethyl 5-benzoyl-1-phenyl orotinate, Add dropwise 5 ml of ethylene chloride containing 0.56 g of triethylamine at room temperature, then add p-tolylisocyanate.
10 ml of ethylene chloride containing 0.80 g was added dropwise. The mixture was heated and reacted under reflux for 2.5 hours. After the reaction, the resulting reaction product mixture is filtered,
8-benzoyl-6-phenyl-2-(p-tolyl)-1,2,3,5,6,7-hexahydro-
1,3,5,7-tetraoxoimidazo[1,5
-C] 0.44 g of pyrimidine crystals were obtained. This was recrystallized from acetonitrile to obtain colorless crystals with a decomposition point of 355°C. The elemental analysis values are shown below. C H N Analytical value 69.26 3.86 9.15 Calculated value 69.18 3.79 9.31 (as C ₂₆ H ₁₇ N ₃ O ₅ ) Example 21 (Compound No. 37) 5-benzoyl-1-(p-methoxyphenyl) ethyl orotate 1.00 g ethylene chloride containing
25 ml was added dropwise at room temperature to 10 ml of ethylene chloride containing 0.51 g of triethylamine, followed by 1.19 g of 3,5-dichlorophenyl isocyanate.
The mixture was allowed to react for one day with stirring at room temperature. After the reaction, the resulting reaction product mixture is filtered,
8-benzoyl-2-(3,5-dichlorophenyl)-6-(p-methoxyphenyl)-1,2,
3,5,6,7-hexahydro-1,3,5,7
-0.47 g of crystals of tetraoxoimidazo[1,5-C]pyrimidine were obtained. This was recrystallized from ethylene chloride to obtain yellow crystals with a decomposition point of 312-320°C.
The elemental analysis values are shown below. C H N Cl Analytical value 58.24 2.73 7.86 13.06 Calculated value 58.23 2.82 7.83 13.22 (as C ₂₆ H ₁₅ Cl ₂ N ₃ O ₆ ) Example 22 (Compound No. 38) 5-benzoyl-1-(3,5-dichloroph) Benzene 20 containing 1.00 g of ethyl) orotate
ml of benzene containing 0.47 g of triethylamine was added dropwise at room temperature, and then 10 ml of benzene containing 0.77 g of p-tolylisocyanate was added dropwise. The mixture was heated and reacted under reflux for 10 hours. After the reaction, the resulting reaction product mixture is filtered,
8-benzoyl-6-(3,5-dichlorophenyl)-2-(p-tolyl)-1,2,3,5,
Crystals of 6,7-hexahydro-1,3,5,7-tetraoxoimidazo[1,5-C]pyrimidine
0.78g was obtained. This was recrystallized from ethylene chloride to obtain pale yellow crystals with a decomposition point of 335°C. The elemental analysis values are shown below. C H N Cl Analytical value 60.52 3.09 7.84 13.64 Calculated value 60.02 2.91 8.08 13.63 (as C ₂₆ H ₁₅ Cl ₂ N ₃ O ₅ ) Example 23 (Compound No. 40) Ethyl 1-(n-butyl)-5-cyanoorotate To 30 ml of ethylene chloride containing 1.58 g and 0.66 g of triethylamine was added dropwise at room temperature 20 ml of ethylene chloride containing 1.59 g of p-tolylisocyanate. The mixture was allowed to react for 8 hours with stirring at room temperature. After the reaction, the resulting reaction product mixture is filtered,
6-(n-butyl)-8-cyano-2-(p-tolyl)-1,2,3,5,6,7-hexahydro-1,3,5,7-tetraoxoimidazo[1,
0.36 g of crystals of 5-C]pyrimidine were obtained. This was recrystallized from ethylene chloride to obtain colorless bulk crystals with a decomposition point of 276°C. The elemental analysis values are shown below. C H N Analytical value 61.07 4.59 15.11 Calculated value 61.36 4.58 15.90 (as C ₁₈ H ₁₆ N ₄ O ₄ ) Example 24 (Compound No. 41) Ethyl 5-cyano-1-phenylorotate
1.08 g of phenyl isocyanate at room temperature in 30 ml of ethylene chloride containing 1.17 g of triethylamine and 0.46 g of triethylamine.
It was added dropwise to 20 ml of ethylene chloride containing g. The mixture was heated and reacted under reflux for 11 hours. After the reaction, the resulting reaction product mixture is filtered,
8-cyano-2,6-diphenyl-1,2,3,
0.24 g of crystals of 5,6,7-hexahydro-1,3,5,7-tetraoxoimidazo[1,5-C]pyrimidine was obtained. This was recrystallized from acetonitrile to obtain colorless needle crystals with a decomposition point of 325°C. The elemental analysis values are shown below. C H N Analytical value 63.79 2.95 15.95 Calculated value 63.69 2.81 15.64 (as C ₁₉ H ₁₀ N ₄ O ₄ ) Example 25 (Compound No. 42) Acetonitrile containing 1.00 g of ethyl 5-fluoroorotate and 2.16 mmol of tetraethylammonium fluoride 5 ml of acetonitrile containing 1.57 g of n-hexyl isocyanate and 0.50 g of triethylamine was added dropwise to 45 ml. The mixture was heated and reacted under reflux for 5.5 hours. After the reaction, the resulting reaction product mixture was concentrated under reduced pressure. Add 100ml of isopropyl ether and water to the residue.
Add 20 ml of 8-fluoro-2-(n-
1.29 g of crystals of (hexyl)-1,2,3,5,6,7-hexahydro-1,3,5,7-tetraoxoimidazo[1,5-C]pyrimidine were obtained.
This is recrystallized from acetonitrile and has a melting point of 278 ~
Yellow granular crystals at 284°C were obtained. The elemental analysis values are shown below. C H N Analytical value 51.04 4.97 14.78 Calculated value 50.88 4.98 14.83 (as C ₁₂ H ₁₄ FN ₃ O ₄ ) Example 26 (Compound No. 44) In 30 ml of acetonitrile containing 0.85 g of ethyl 5-fluoroorotate and 0.85 g of triethylamine,
10 ml of acetonitrile containing 1.40 g of benzyl isocyanate were added dropwise at room temperature. The mixture was heated and reacted under reflux for 1 hour. After the reaction, the resulting reaction product mixture was concentrated under reduced pressure. Add 80ml of isopropyl ether and 30ml of water to the residue.
ml of 2-benzyl-8-fluoro-1,2,3,5,6,7-hexahydro-1,
3,5,7-tetraoxoimidazo[1,5-
C] 1.06 g of pyrimidine crystals were obtained. This was recrystallized from acetonitrile to obtain colorless plate-like crystals with a melting point of 292-296°C. The elemental analysis values are shown below. C H N Analytical value 54.07 2.86 14.71 Calculated value 53.99 2.79 14.53 (as C ₁₃ H ₈ FN ₃ O ₄ ) Example 27 (Compound No. 46) Add p- to 30 ml of acetonitrile containing 0.75 g of ethyl 5-fluoroorotate at room temperature. 10 ml of acetonitrile containing 1.60 g of tolylisocyanate and 0.75 g of triethylamine was added dropwise. The mixture was allowed to react for 17 hours with stirring at room temperature. After the reaction, the resulting reaction product mixture is filtered,
The liquid was concentrated under reduced pressure. Add 10ml of ethylene chloride to the residue.
Add 30 ml of isopropyl ether and filter.
-Fluoro-2-(p-tolyl)-1,2,3,
0.83 g of crystals of 5,6,7-hexahydro-1,3,5,7-tetraoxoimidazo[1,5-C]pyrimidine were obtained. This was recrystallized from acetonitrile to obtain colorless needle crystals with a melting point of 332-338°C.
The elemental analysis values are shown below. C H N Analytical value 54.40 2.78 15.05 Calculated value 53.99 2.79 14.53 (as C ₁₃ H ₈ FN ₃ O ₄ ) Example 28 (Compound No. 50) Ethyl 1-benzyl-5-fluoroorotate
Add 0.78g of p-tolylisocyanate to 30ml of ethylene chloride containing 0.54g of triethylamine at room temperature.
10 ml of ethylene chloride containing 0.71 g was added dropwise. The mixture was allowed to react for one day with stirring at room temperature. After the reaction, the resulting reaction product mixture was filtered and
-benzyl-8-fluoro-2-(p-tolyl)
-1,2,3,5,6,7-hexahydro-1,
3,5,7-tetraoxoimidazo[1,5-
C] 0.54 g of pyrimidine crystals were obtained. This was recrystallized from ethylene chloride to obtain colorless needle crystals with a decomposition point of 140-142°C. The elemental analysis values are shown below. N Analytical value 11.18 Calculated value 11.08 (as C ₂₀ H ₁₄ FN ₃ O ₄ ) Example 29 (Compound No. 52) Ethyl 5-fluoro-1-phenyl orotate
To 50 ml of ethylene chloride containing 1.15 g and 0.84 g of triethylamine was added 1.55 g of 3,5-dichlorophenyl isocyanate at room temperature. The mixture was allowed to react for one day with stirring at room temperature. After the reaction, the resulting reaction product mixture is filtered,
2-(3,5-dichlorophenyl)-8-fluoro-6-phenyl-1,2,3,5,6,7-hexahydro-1,3,5,7-tetraoxoimidazo[1,5- C] 0.64 g of pyrimidine crystals were obtained. This is recrystallized with ethylene chloride to reach the decomposition point.
Colorless microacicular crystals were obtained at 326°C. The elemental analysis values are shown below. C H N Analytical value 51.75 1.99 10.11 Calculated value 51.45 1.92 10.00 (as C ₁₈ H ₈ Cl ₂ FN ₃ O ₄ ) Example 30 (Compound No. 53) 2.00 g of ethyl 5-chloroorotate and 9.01 mmol of tetraethylammonium fluoride. Add 0.99 g of triethylamine to 40 ml of acetonitrile, then add 1.98 g of isopropyl isocyanate.
20 ml of acetonitrile was added dropwise. The mixture was heated and reacted under reflux for 5 hours. After the reaction, the resulting reaction product mixture was concentrated under reduced pressure. 30 ml of ethylene chloride and 30 ml of water were added to the residue, filtered, and 8-chloro-2-isopropyl-1,
2,3,5,6,7-hexahydro-1,3,
1.62 g of crystals of 5,7-tetraoxoimidazo[1,5-C]pyrimidine were obtained. This was recrystallized from ethylene chloride to obtain colorless crystals with a melting point of 268-270°C. The elemental analysis values are shown below. C H N Analytical value 41.67 3.18 16.27 Calculated value 41.96 3.13 16.31 (as C ₉ H ₈ ClN ₃ O ₄ ) Example 31 (Compound No. 55) Acetonitrile containing 2.00 g of ethyl 5-chloroorotate and 9.6 mmol of tetraethylammonium fluoride 20ml triethylamine at room temperature
Add 1.83g, then 2.15g of allyl isocyanate
20 ml of acetonitrile containing g was added dropwise.
The mixture was heated and reacted under reflux for 6 hours. After the reaction, the resulting reaction product mixture was concentrated under reduced pressure. 30 ml of ethylene chloride and 30 ml of water were added to the residue and filtered to give 2-allyl-8-chloro-1,2,
3,5,6,7-hexahydro-1,3,5,7
-1.65 g of crystals of tetraoxoimidazo[1,5-C]pyrimidine were obtained. This was recrystallized from ethylene chloride to obtain colorless needle crystals with a decomposition point of 239-240°C. The elemental analysis values are shown below. C H N Analytical value 41.65 2.51 16.20 Calculated value 42.29 2.37 16.44 (as C ₉ H ₆ ClN ₃ O ₄ ) Example 32 (Compound No. 60) In 40 ml of ethylene chloride containing 1.96 g of ethyl 5-bromoorotate and 0.85 g of triethylamine, 20 ml of ethylene chloride containing 1.78 g of phenyl isocyanate were added dropwise at room temperature. The mixture was allowed to react for one day with stirring at room temperature. After the reaction, the resulting reaction product mixture was concentrated under reduced pressure. Add 40ml of benzene, 10ml of 1N hydrochloric acid and water to the residue.
Add 20 ml and filter, 8-bromo-2-phenyl-1,2,3,5,6,7-hexahydro-1,
3,5,7-tetraoxoimidazo[1,5-
C] 2.40 g of pyrimidine crystals were obtained. This was recrystallized from ethylene chloride to obtain pale yellow crystals with a decomposition point of 284-285°C. The elemental analysis values are shown below. C H N Br Analytical value 43.01 1.81 12.49 24.01 Calculated value 42.88 1.80 12.50 23.77 (as C ₁₂ H ₁₆ BrN ₃ O ₄ ) Example 33 (Compound No. 61) 1.10 g of ethyl 5-bromo-1-isopropylorotate and 0.73 g of triethylamine 0.86 g of phenyl isocyanate at room temperature in 20 ml of benzene containing g
210 ml of benzene containing was added dropwise. The mixture was allowed to react for one day with stirring at room temperature. After the reaction, the resulting reaction product mixture is filtered,
8-Bromo-6-isopropyl-2-phenyl-
1,2,3,5,6,7-hexahydro-1,
3,5,7-tetraoxoimidazo[1,5-
C] 0.59 g of pyrimidine crystals were obtained. This was recrystallized from ethylene chloride to obtain colorless crystals with a melting point of 301°C. The elemental analysis values are shown below. C H N Br Analytical value 47.84 3.20 11.15 20.91 Calculated value 47.64 3.20 11.11 21.13 (as C ₁₅ H ₁₂ BrN ₃ O ₄ ) Example 34 (Compound No. 63) Ethyl 5-bromo-1-phenylorotate
In 40 ml of ethylene chloride containing 2.71 g of triethylamine and 1.62 g of triethylamine, add 1.90 phenyl isocyanate at room temperature.
10 ml of ethylene chloride containing g were added dropwise. The mixture was allowed to react for one day with stirring at room temperature. After the reaction, the resulting reaction product mixture is filtered,
8-bromo-2,6-diphenyl-1,2,3,
2.85 g of crystals of 5,6,7-hexahydro-1,3,5,7-tetraoxoimidazo[1,5-C]pyrimidine were obtained. This was recrystallized from ethylene chloride to obtain colorless needle crystals with a decomposition point of 373°C. The elemental analysis values are shown below. C H N Analyzed value 49.63 2.61 8.63 Calculated value 49.43 2.62 9.10

Claims (1)

[Claims] 1 formula [In the formula, R ¹ is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a phenyl group, an alkoxycarbonyl group having 2 to 5 carbon atoms, an aliphatic acyl group having 2 to 5 carbon atoms, a benzoyl group, a cyano group, or Represents a halogen atom, R ² is a hydrogen atom, an alkyl group having 1 to 10 carbon atoms,
Allyl group, cyclohexyl group, benzyl group, or [Formula] (R ⁴ represents an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, or a halogen atom, and n is 0, 1 or 2. )
represents a group represented by the following, and R ³ represents an alkyl group having 1 to 4 carbon atoms. ] and the orotate ester represented by the formula R ⁵ -N=C=O [wherein R ⁵ is an alkyl group having 1 to 10 carbon atoms, an allyl group, a cyclohexyl group, a benzyl group, or [Formula] (R ⁴ and n each have the same meaning as above. ] isocyanate represented by
characterized in that the reaction is carried out in the presence of an amine and/or a quaternary ammonium fluoride. A method for producing imidazopyrimidines represented by the formula (wherein R ¹ , R ² and R ⁵ each have the same meanings as above).