JPS6132311B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to the parent compound, the alkali metal salt of 5-carboxyorotic acid. More specifically, the present invention provides the formula [In the formula, Me represents an alkali metal, and R ¹ is an alkyl group having 1 to 4 carbon atoms, an allyl group, a cyclohexyl group, a benzyl group, or

[Formula] (In the formula, R ² represents an alkyl group having 1 to 4 carbon atoms, an alkoxyl group having 1 to 4 carbon atoms, or a halogen atom, and n is 0, 1, 2, or 3.) shows. ] It is an alkali metal salt of 5-carboxyorotic acid represented by: The 5-carboxyorotic acid of the present invention is suitable for agricultural chemicals,
It is useful as a medicine and also as an intermediate thereof, and is particularly effective as a fungicide as an agricultural chemical, and is effective against sclerotium of yellow cucumbers and white leaf blight of rice. The physical properties of representative examples of the present invention are shown below.

【table】

[Table] The alkali metal salt of 5-carboxyorotic acid of the present invention can be synthesized, for example, according to the following reaction formula. In addition, in the above formula, R ¹ is the same as the definition in [], and R ³ , R ⁴ and R ⁵ have 1 carbon number.
~4 alkyl group. Reaction of formula (1) After reacting the cyanoformic acid ester represented by the formula [] with the malonic acid diester represented by the formula [] in the presence of a titanium or tin halide at a temperature in the range of -10 to 100°C. By treating the reaction product mixture with water or an acidic aqueous solution, an α,β-unsaturated-α-amino acid ester represented by the formula [] is produced. The amount of malonic acid diester used is at least equimolar to the cyanoformic acid ester. It is sufficient to use about 1 mole of titanium or tin halide per mole of cyanoformate. The reaction can be carried out in the presence or absence of a solvent such as an aromatic hydrocarbon or a halogenated hydrocarbon. Reaction of formula (2) The α,β-unsaturated-α-amino acid ester represented by the formula [] and the isocyanate represented by the formula [] are combined in the presence of quaternary ammonium fluoride or quaternary ammonium fluoride and a tertiary amine. By reacting at a temperature in the range of 20 to 100°C, a hydantoin derivative represented by the formula [] is produced. In this reaction, aromatic hydrocarbons, halogenated hydrocarbons, ethers, etc. are preferably used as reaction solvents. The amounts of isocyanate and quaternary ammonium fluoride used are α,β-unsaturated-α
-2 to 1 mole of amino acid ester, respectively
Preferably it is 3 mol and 0.1 to 1 mol. Reaction of formula (3) The hydantoin derivative represented by formula [] is
After reacting with alkali hydroxide in water, alcohol or a mixed solvent thereof at room temperature or under heating,
By adding a mineral acid to the reaction product mixture, a 5-carboxyorotic acid metal salt represented by the formula [] is produced. As the alkali hydroxide, sodium hydroxide, potassium hydroxide and lithium hydroxide are preferably used, and the amount used is preferably 3 to 5 mol per 1 mol of the hydantoin derivative. The desired product, the alkali metal salt of 5-carboxyorotic acid, can be isolated from the reaction product mixture by isolation methods known per se. Next, a synthesis example will be shown. Synthesis Example 1 (Compound No. 2) Ethylene chloride 100 containing 108.7 mmol of tin tetrachloride
60 ml of benzene containing 108.7 mmol of diethyl malonate per ml and then 60 ml of benzene containing 108.7 mmol of ethyl cyanoformate were added dropwise, and the mixture was reacted under reflux for 1 hour. Add 100% water to the reaction mixture under ice cooling.
ml was added dropwise and stirred for 1 hour. The reaction product mixture was separated and the aqueous layer was extracted three times with 40 ml of chloroform each time. A solution of the extract added to the organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. 50 ml of n-hexane was added to the residue, filtered, and 1-amino-
26.71 g of crystals of 1,2,2-triethoxycarbonylethylene (hereinafter abbreviated as ATE) were obtained.
This was recrystallized from diisopropyl ether to obtain 18.52 g of colorless prismatic crystals with a melting point of 69.5-70°C. Ethylene chloride containing 4.6 mmol of tetraethylammonium fluoride and 20.0 mmol of ATE
Add 50.0 mmol of triethylamine to 80 ml,
Then, 20 ml of ethylene chloride containing 50.0 mmol of n-butyl isocyanate was added dropwise, and the mixture was reacted for 1 hour at room temperature with stirring. 50% water to reaction product mixture
ml, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was distilled under reduced pressure to obtain 1.12 g of N-(n-butyl)carbamic acid ethyl ester (boiling point 73° C./3.5 mmHg) as a fraction. The distillation residue was recrystallized from n-hexane to obtain 5.02 g of crystals of 5-di(ethoxycarbonyl)methylene-3-(n-butyl)hydantoin (melting point: 59-61°C). 5-di(ethoxycarbonyl)methylene-3-
To 30 ml of ethanol containing 10.5 mmol of (n-butyl)hydantoin was added 10 ml of water containing 42 mmol of potassium hydroxide at room temperature, and the mixture was reacted under reflux for 2 hours. 42 ml of 1N hydrochloric acid was added to the reaction mixture under ice cooling, and the mixture was filtered to remove 5-carboxy-
Crystals of 1-(n-butyl)orotate potassium salt
1.8g was obtained. Combine this with 1 volume part of water and 3 parts of ethanol.
Recrystallization was performed using 80 ml of a mixed solvent consisting of parts by volume to obtain 1.13 g of colorless needle-like crystals with a melting point of 201-203°C (decomposition). The elemental analysis values are shown below. C H N Analytical value 43.75 4.14 10.27 Calculated value 43.64 4.21 10.18 (as C ₂₀ H ₂₃ N ₄ O ₁₂ K) Synthesis example 2 (compound number 6) Synthesized in the same manner as in synthesis example 1
Ethylene chloride 50 containing 10.0 mmol ATE and 2.5 mmol tetraethylammonium fluoride
ml, 20 ml of ethylene chloride containing 25.0 mmol of benzyl isocyanate was added dropwise at room temperature, and then 20.0 mmol of triethylamine was added thereto, followed by reaction under reflux for 1 hour. After concentrating the reaction product mixture under reduced pressure and adding 50 ml of isopropanol to the residue,
1.96 g of colorless needle crystals (melting point: 149-151°C) of 5-di(ethoxycarbonyl)methylene-3-benzylhydantoin were obtained. 5-di(ethoxycarbonyl)methylene-3-
To 25 ml of ethanol containing 3.1 mmol of benzylhydantoin was added 25 ml of water containing 12.6 mmol of potassium hydroxide at room temperature, and the mixture was reacted under reflux for 2 hours. The reaction product mixture was concentrated under reduced pressure, and a solution of the residue dissolved in 20 ml of water was mixed with 11 ml of 1N sulfuric acid and 60 ml of water.
ml and filtered to obtain 0.73 g of crystals of 5-carboxy-1-benzylorotate potassium salt. Recrystallize this with water to obtain the melting point
0.37 g of colorless needle crystals having a temperature of 200-201 (decomposition) C were obtained. The elemental analysis values are shown below. C H N Analytical value 50.61 3.08 8.97 Calculated value 50.49 3.10 9.06 (as C ₂₆ H ₁₉ N ₄ O ₁₂ K) Synthesis example 3 (compound number 10) Synthesized in the same manner as in synthesis example 1
ATE42.4 mmol and tetra(n-butyl)
Add phenyl isocyanate to 60 ml of ethylene chloride containing 8.6 mmol of ammonium fluoride at room temperature.
40 ml of ethylene chloride containing 101.8 mmol was added dropwise, and the mixture was reacted under reflux for 1 hour. The reaction product mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give 5-di(ethoxycarbonyl)methylene-3.
- Colorless needle-like crystals of phenylhydantoin (melting point
12.14g (167°C) was obtained. 5-di(ethoxycarbonyl)methylene-3-
To 30 ml of ethanol containing 9.0 mmol of phenylhydantoin was added 20 ml of water containing 36.1 mmol of sodium hydroxide under reflux, and the mixture was reacted for 1 hour. Add 40 ml of 1N hydrochloric acid to the reaction mixture under ice cooling.
was added and filtered to obtain 2.53 g of crystals of 5-carboxy-1-phenylorotic acid sodium salt. This was recrystallized from water to obtain 1.00 g of colorless crystals with a melting point of 217-218°C (decomposition). This crystal was confirmed to be a monohydrate of 5-carboxy-1-phenylorotic acid sodium salt from the following elemental analysis values. C H N Analytical value 48.65 2.99 9.45 Calculated value 48.66 2.89 9.46 (as C ₂₄ H ₁₇ N ₄ O ₁₃ Na) Synthesis Example 4 (Compound No. 14) Synthesized in the same manner as in Synthesis Example 1
Ethylene chloride 80 containing 20.0 mmol ATE and 3.8 mmol tetraethylammonium fluoride
20 ml of ethylene chloride containing 50.0 mmol of p-tolylisocyanate was added dropwise to the solution, and the mixture was reacted under reflux for 3 hours. The reaction product mixture is concentrated under reduced pressure,
50 ml of diisopropyl ether was added to the residue, filtered, and 5-di(ethoxycarbonyl)methylene-3
6.59 g of crystals of -(p-tolyl)hydantoin were obtained. This is recrystallized from ethanol and has a melting point of 154 ~
4.67 g of colorless needle crystals were obtained at 155°C. 5-di(ethoxycarbonyl)methylene-3-
To 30 ml of ethanol containing 7.2 mmol of (p-tolyl)hydantoin was added 10 ml of water containing 28.8 mmol of lithium hydroxide at room temperature, and the mixture was reacted under reflux for 1 hour. The reaction product mixture is concentrated under reduced pressure,
20 ml of water was added to the residue, filtered, and N,N'-di(p
-Tolyl) urea crystals (0.05 g) were obtained. The solution was added to 20 ml of 6N sulfuric acid and filtered to obtain 1.61 g of crystals of 5-carboxy-1-(p-tolyl)orotate lithium salt. This is recrystallized with water and the melting point is
0.63 g of colorless crystals having a temperature of 194-196°C (decomposition) were obtained. The elemental analysis values are shown below. C H N Analytical value 53.67 3.55 9.54 Calculated value 53.26 3.27 9.55 (as C ₂₆ H ₁₉ N ₄ O ₁₂ Li) Synthesis example 5 (compound number 15) Synthesized in the same manner as in synthesis example 1
To 80 ml of ethylene chloride containing 20.0 mmol of ATE and 4.2 mmol of benzyltrimethylammonium fluoride, 20 ml of ethylene chloride containing 50.7 mmol of p-chlorophenyl isocyanate was added dropwise at room temperature, and the mixture was reacted under reflux for 2 hours. . The reaction product mixture was concentrated under reduced pressure, and 30 ml of ethanol was added to the residue, which was then filtered to obtain 6.89 g of crystals of 5-di(ethoxycarbonyl)methylene-3-(p-chlorophenyl)hydantoin. This was recrystallized from ethanol to obtain 5.50 g of colorless needle crystals with a melting point of 161.5-162°C. 5-di(ethoxycarbonyl)methylene-3-
To 30 ml of ethanol containing 12.3 mmol of (p-chlorophenyl)hydantoin was added 10 ml of water containing 49.0 mmol of sodium hydroxide at room temperature, and the mixture was reacted under reflux for 1 hour. The reaction product mixture was concentrated under reduced pressure, 10 ml of water was added to the residue, and then filtered.
Crystals of N,N'-di(p-chlorophenyl)urea
0.28g was obtained. The solution was added to 49 ml of 1N hydrochloric acid and filtered to give 3.38 mL of crystals of 5-carboxy-1-(P-chlorophenyl)orotate sodium salt.
I got g. This is recrystallized with water and has a melting point of 237-238.
(Decomposition) 2.35 g of colorless crystals were obtained. From the following elemental analysis values, this crystal is 5-carboxy-1-
It was confirmed that it was a monohydrate of (p-chlorophenyl)orotate sodium salt. C H N Cl Analytical value 43.70 2.03 8.53 11.07 Calculated value 43.60 2.29 8.47 10.72 (as C ₂₄ H ₁₅ Cl ₂ N ₄ O ₁₃ Na)

Claims (1)

[Claims] 1 formula [In the formula, Me represents an alkali metal, R ¹ is an alkyl group having 1 to 4 carbon atoms, an allyl group, a cyclohexyl group, a benzyl group, or [Formula] (In the formula, R ² is an alkyl group having 1 to 4 carbon atoms) group, an alkoxyl group having 1 to 4 carbon atoms, or a halogen atom, and n is 0, 1, 2 or 3). ] 5-carboxyorotic acid alkali metal salt represented by: